Heterocyclic Compounds and Their Application in Therapy

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (15 April 2023) | Viewed by 91381

Special Issue Editors


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Guest Editor
INSA Rouen Normandie, Univ. Rouen Normandie, CNRS UMR 6014 COBRA, FR 3038, F-76000 Rouen, France
Interests: chemistry of heterocyclic compounds; microwave-assisted chemistry; sustainable methodologies; green chemistry applied to bioactive compounds: kinase inhibitors; Alzheimer's disease; down syndrome; cancer
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Cibles et Médicaments des Infections et de l’immunité, Nantes Université, IICiMed, UR 1155, 44000 Nantes, France
Interests: design, synthesis and biological evaluation of heterocyclic compounds for therapeutic purposes (mycology, parasitology, bacteriology and cancer); inhibitors of kinase signaling pathways; ADMET properties of molecules of biological interest
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Heterocycles are present in numerous organic compounds of interest in biology, pharmacology, and medicine. Aromatic and non-aromatic molecules are still one of the largest areas of research in organic and medicinal chemistry. Exploring novel techniques or methods for synthesizing and functionalizing these compounds has been boosted, until becoming one of the major axes of sustainable chemistry. Heterocycles exhibit unique structures leading to several applications in the design of drugs. Presence of heteroatoms (e.g., N, S, and O) in the cyclic molecular structures results in significant physicochemical properties. Hydrogen-bond donors and acceptors in these rigid frameworks allow hydrogen-bond interactions with receptors and/or target enzymes, enhancing binding affinity and improving therapeutic potency. Heterocycles can also be involved in the design of prodrugs and can modulate the lipophilicity of bioactive molecules, thus varying their pharmacokinetic and pharmaceutical properties. This Special Issue aims to review recent developments in the design, synthesis, and pharmaceutical properties of natural products and synthetic compounds containing aromatic heterocyclic systems. 

Prof. Dr. Thierry Besson
Prof. Dr. Pascal Marchand
Guest Editors

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Keywords

  • medicinal chemistry
  • bioactive heterocyclic compounds
  • chemical space
  • chemical tools
  • innovative and sustainable synthetic routes
  • molecular modelling studies
  • pharmacological properties
  • prodrugs: design and development
  • in vitro and in vivo studies

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Published Papers (30 papers)

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19 pages, 3039 KiB  
Article
Synthesis, Anticancer, Antimicrobial and Antioxidant Potential of Novel 4-(Substituted phenyl-1,3,4-oxadiazol/thiadiazol-2-yl)-4-(4-substituted phenyl) Azetidin-2-One Derivatives
by Davinder Kumar, Navidha Aggarwal, Virender Kumar, Harsh Kumar, Aakash Deep, Shabana Bibi, Hitesh Chopra, Rakesh Kumar Marwaha, Abdulrahman Alshammari, Metab Alharbi and Abdul Hayee
Pharmaceuticals 2023, 16(4), 517; https://doi.org/10.3390/ph16040517 - 30 Mar 2023
Cited by 2 | Viewed by 1991
Abstract
By exploiting the ample biological potential of 1,3,4-oxadiazole/thiadiazole ring, 4-substitutedphenyl-1,3,4-oxadiazol/Thiadiazol-2-yl)-4-(4-substitutedphenyl) azetidin-2-one derivatives were prepared. Various substituted azetidin-2-one derivatives have been identified as immunostimulating and antimicrobial, as well as their antioxidant activity. 2-amino 1,3,4 oxadiazole/thiadiazole conjugates were synthesized by mixing semi/thio carbazides and sodium [...] Read more.
By exploiting the ample biological potential of 1,3,4-oxadiazole/thiadiazole ring, 4-substitutedphenyl-1,3,4-oxadiazol/Thiadiazol-2-yl)-4-(4-substitutedphenyl) azetidin-2-one derivatives were prepared. Various substituted azetidin-2-one derivatives have been identified as immunostimulating and antimicrobial, as well as their antioxidant activity. 2-amino 1,3,4 oxadiazole/thiadiazole conjugates were synthesized by mixing semi/thio carbazides and sodium acetate with water and stirring well, followed by adding aldehydes in methanol at room temperature. Acetate (glacial) was used as the catalyst to produce Schiff’s bases (intermediates) by treating substituted aldehydes with 2-amino 1,3,4 oxadiazole/thiadiazole(s). Using the mixture of triethylamine (dropwise) and chloroacetylchloride with vigorous stirring, 4-substitutedphenyl-1,3,4-oxadiazol/Thiadiazol-2-yl)-4-(4-substitutedphenyl) azetidin-2-one derivatives were prepared. The newly synthesized conjugates were evaluated for their anticancer potential using MCF-7 cell lines. Amoxicillin and fluconazole were used as reference drugs to determine their antimicrobial activity. Synthesized derivatives were evaluated for their antioxidant properties using 2-diphenyl-1-picrylhydrazyl (DPPH). In vitro cytotoxicity screening (MTTS assay) revealed that derivatives AZ-5, 9, 10, 14 and 19 demonstrated high efficacy with the percentage of inhibition at different concentration ranges (0.1 μM, 0.5 μM, 1 μM, 2 μM) of 89% to 94% μM as compared to doxorubicin as standard drug. The antimicrobial study indicated that compounds AZ-10, 19, and AZ-20 were found to have significant antimicrobial potential with MIC ranges of 3.34 µM to 3.71 µM in comparison to reference drugs having 4.29 µM to 5.10 µM. Based on antioxidant screening, most of the synthetic derivatives showed greater stability and effectiveness than the standard drug. According to the antioxidant screening, compounds AZ-5 and AZ-15 (IC50 = 45.02 μg/mL and 42.88 μg/mL, respectively) showed the greatest potency, as compared to ascorbic acid (IC50 = 78.63 μg/mL). Structure-activity relationship (SAR) studies of synthesized novel derivatives revealed that para-substituted halogen and nitro derivatives have remarkable potential against MCF-7 cancer cell lines and different microbial strains. Current evidence indicates that the synthesized derivatives may be promising candidates for use in the prevention and treatment of these infections. These synthesized compounds require further mechanism-based research to understand how they interact with the cells. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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23 pages, 4597 KiB  
Article
Diverse Biological Activity of Benzofuroxan/Sterically Hindered Phenols Hybrids
by Elena Chugunova, Elmira Gibadullina, Kirill Matylitsky, Baurat Bazarbayev, Margarita Neganova, Konstantin Volcho, Artem Rogachev, Nurgali Akylbekov, Hoang Bao Tran Nguyen, Alexandra Voloshina, Anna Lyubina, Syumbelya Amerhanova, Victor Syakaev, Alexander Burilov, Nurbol Appazov, Mukhtar Zhanakov, Leah Kuhn, Oleg Sinyashin and Igor Alabugin
Pharmaceuticals 2023, 16(4), 499; https://doi.org/10.3390/ph16040499 - 28 Mar 2023
Cited by 4 | Viewed by 2088
Abstract
Combining two pharmacophores in a molecule can lead to useful synergistic effects. Herein, we show hybrid systems that combine sterically hindered phenols with dinitrobenzofuroxan fragments exhibit a broad range of biological activities. The modular assembly of such phenol/benzofuroxan hybrids allows variations in the [...] Read more.
Combining two pharmacophores in a molecule can lead to useful synergistic effects. Herein, we show hybrid systems that combine sterically hindered phenols with dinitrobenzofuroxan fragments exhibit a broad range of biological activities. The modular assembly of such phenol/benzofuroxan hybrids allows variations in the phenol/benzofuroxan ratio. Interestingly, the antimicrobial activity only appears when at least two benzofuroxan moieties are introduced per phenol. The most potent of the synthesized compounds exhibit high cytotoxicity against human duodenal adenocarcinoma (HuTu 80), human breast adenocarcinoma (MCF-7), and human cervical carcinoma cell lines. This toxicity is associated with the induction of apoptosis via the internal mitochondrial pathway and an increase in ROS production. Encouragingly, the index of selectivity relative to healthy tissues exceeds that for the reference drugs Doxorubicin and Sorafenib. The biostability of the leading compounds in whole mice blood is sufficiently high for their future quantification in biological matrices. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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29 pages, 3290 KiB  
Article
Antidiabetic Potential of Novel 1,3,5-Trisubstituted-2-Thioxoimidazloidin-4-One Analogues: Insights into α-Glucosidase, α-Amylase, and Antioxidant Activities
by Salma M. Khirallah, Heba M. M. Ramadan, Hossam Aladl Aladl Aladl, Najla O. Ayaz, Lina A. F. Kurdi, Mariusz Jaremko, Samar Zuhair Alshawwa and Essa M. Saied
Pharmaceuticals 2022, 15(12), 1576; https://doi.org/10.3390/ph15121576 - 17 Dec 2022
Cited by 9 | Viewed by 1947
Abstract
As the ninth leading cause of death globally, diabetes mellitus (DM) is considered to be the worst chronic metabolic disease requiring an enormous need for healthcare with over 578 million expected cases by 2023. Several recent findings have demonstrated that mediating the activity [...] Read more.
As the ninth leading cause of death globally, diabetes mellitus (DM) is considered to be the worst chronic metabolic disease requiring an enormous need for healthcare with over 578 million expected cases by 2023. Several recent findings have demonstrated that mediating the activity of carbohydrate-hydrolyzing enzymes, including α-amylase and α-glucosidase, could be a potential strategy for managing the development of DM. In the presented study, a novel set of 1,3,5-trisubstituted-2-thioxoimidazolidin-4-ones was designed, synthesized, and characterized. The antidiabetic activity of the synthesized compounds was explored by assessing their inhibitory activity toward α-amylase and α-glucosidase enzymes. The results demonstrated that this class of compounds exhibits considerable inhibitory activity toward both α-amylase and α-glucosidase enzymes. Among the synthesized compounds, compound 5a demonstrated the most inhibitory activity with IC50 of 5.08 and µg/mL and 0.21 µg/mL toward α-glucosidase and α-amylase activities, respectively, as compared to the drug Acarbose (IC50 = 5.76 µg/mL and 0.39 µg/mL, respectively). To gain insights into the antidiabetic potential of compound 5a, we assessed the cytotoxic and antioxidant activities. Our findings indicated that compound 5a displays considerable cytotoxicity toward WI-38 cells with an IC50 of 88.54 µg/mL, as compared to the drug Celecoxib (IC50 = 93.05 µg/mL). Further, compound 5a exhibited a high scavenging activity toward 2,2-Diphenyl1-picrylhydrazyl (DPPH) free radicals (IC50 = 51.75 µg/mL) and showed a low potential to produce ROS as indicated by the monitoring of the generated H2O2 (132.4 pg/mL), as compared to Trolox (IC50 = 58.09 µg/mL) and Celecoxib (171.6 pg/mL). Finally, we performed extensive molecular modeling studies to affirm the binding affinity of this class of compounds to the binding pocket of α-amylase and α-glucosidase enzymes. Collectively, our findings indicate that this class of compounds, particularly compound 5a, could be utilized as a lead structure for the development of novel compounds with potential antidiabetic and antioxidant activities. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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25 pages, 19824 KiB  
Article
Synthesis and Biological Evaluation of a Fused Structure of Indolizine and Pyrrolo[1,2-c]pyrimidine: Identification of Its Potent Anticancer Activity against Liver Cancer Cells
by Seonghyeon Nam, Yechan Lee, So-Hyeon Park, Wan Namkung and Ikyon Kim
Pharmaceuticals 2022, 15(11), 1395; https://doi.org/10.3390/ph15111395 - 12 Nov 2022
Cited by 3 | Viewed by 1796
Abstract
A highly efficient approach to a new indolizine scaffold fused with pyrrolo[1,2-c]pyrimidine was achieved via one-pot three-component coupling followed by an oxidative cyclization reaction. The simple two-step sequence allowed rapid access to various tetracyclic compounds from commercially available starting materials with [...] Read more.
A highly efficient approach to a new indolizine scaffold fused with pyrrolo[1,2-c]pyrimidine was achieved via one-pot three-component coupling followed by an oxidative cyclization reaction. The simple two-step sequence allowed rapid access to various tetracyclic compounds from commercially available starting materials with the formation of five new bonds. Here, we observed the effects of these compounds on cell viability in HepG2, H1299, HT29, AGS, and A549 cancer cell lines. Interestingly, this fused scaffold had more potent anticancer activity in hepatocellular carcinoma HepG2 and Huh7 cells than other cancer cells. In particular, 5r strongly decreased cell viability in HepG2 and Huh7 cells with an IC50 value of 0.22 ± 0.08 and 0.10 ± 0.11 µM, respectively, but had a very weak inhibitory effect on the cell viability of other cancer cell lines. In addition, 5r significantly inhibited cell migration and induced apoptosis in HepG2 and Huh7 cells via the activation of caspase-3 and cleavage of PARP in a dose-dependent manner. Notably, the co-treatment of 5r with gemcitabine resulted in the significant additional inhibition of cell viability in HepG2 and Huh7 cells. Our results suggest that 5r could be used to develop new chemotype anticancer agents against liver cancers. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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19 pages, 4334 KiB  
Article
New Quinoline–Urea–Benzothiazole Hybrids as Promising Antitubercular Agents: Synthesis, In Vitro Antitubercular Activity, Cytotoxicity Studies, and In Silico ADME Profiling
by Rashmika Moodley, Chakes Mashaba, Goitsemodimo H. Rakodi, Nomagugu B. Ncube, Mabuatsela V. Maphoru, Mohammed O. Balogun, Audrey Jordan, Digby F. Warner, Rene Khan and Matshawandile Tukulula
Pharmaceuticals 2022, 15(5), 576; https://doi.org/10.3390/ph15050576 - 5 May 2022
Cited by 14 | Viewed by 2861
Abstract
A series of 25 new benzothiazole–urea–quinoline hybrid compounds were synthesized successfully via a three-step synthetic sequence involving an amidation coupling reaction as a critical step. The structures of the synthesized compounds were confirmed by routine spectroscopic tools (1H and 13C [...] Read more.
A series of 25 new benzothiazole–urea–quinoline hybrid compounds were synthesized successfully via a three-step synthetic sequence involving an amidation coupling reaction as a critical step. The structures of the synthesized compounds were confirmed by routine spectroscopic tools (1H and 13C NMR and IR) and by mass spectrometry (HRMS). In vitro evaluation of these hybrid compounds for their antitubercular inhibitory activity against the Mycobacterium tuberculosis H37Rv pMSp12::GPF bioreporter strain was undertaken. Of the 25 tested compounds, 17 exhibited promising anti-TB activities of less than 62.5 µM (MIC90). Specifically, 13 compounds (6b, 6g, 6ij, 6l, 6op, 6rt, and 6xy) showed promising activity with MIC90 values in the range of 1–10 µM, while compound 6u, being the most active, exhibited sub-micromolar activity (0.968 µM) in the CAS assay. In addition, minimal cytotoxicity against the HepG2 cell line (cell viability above 75%) in 11 of the 17 compounds, at their respective MIC90 concentrations, was observed, with 6u exhibiting 100% cell viability. The hybridization of the quinoline, urea, and benzothiazole scaffolds demonstrated a synergistic relationship because the activities of resultant hybrids were vastly improved compared to the individual entities. In silico ADME predictions showed that the majority of these compounds have drug-like properties and are less likely to potentially cause cardiotoxicity (QPlogHERG > −5). The results obtained in this study indicate that the majority of the synthesized compounds could serve as valuable starting points for future optimizations as new antimycobacterial agents. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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14 pages, 2404 KiB  
Article
Substituted Purines as High-Affinity Histamine H3 Receptor Ligands
by Christian Espinosa-Bustos, Luisa Leitzbach, Tito Añazco, María J. Silva, Andrea del Campo, Alejandro Castro-Alvarez, Holger Stark and Cristian O. Salas
Pharmaceuticals 2022, 15(5), 573; https://doi.org/10.3390/ph15050573 - 4 May 2022
Cited by 1 | Viewed by 2104
Abstract
Continuing with our program to obtain new histamine H3 receptor (H3R) ligands, in this work we present the synthesis, H3R affinity and in silico studies of a series of eight new synthetically accessible purine derivatives. These compounds are [...] Read more.
Continuing with our program to obtain new histamine H3 receptor (H3R) ligands, in this work we present the synthesis, H3R affinity and in silico studies of a series of eight new synthetically accessible purine derivatives. These compounds are designed from the isosteric replacement of the scaffold presented in our previous ligand, pyrrolo[2,3-d]pyrimidine ring, by a purine core. This design also considers maintaining the fragment of bipiperidine at C-4 and aromatic rings with electron-withdrawing groups at N-9, as these fragments are part of the proposed pharmacophore. The in vitro screening results show that two purine derivatives, 3d and 3h, elicit high affinities to the H3R (Ki values of 2.91 and 5.51 nM, respectively). Both compounds are more potent than the reference drug pitolisant (Ki 6.09 nM) and show low toxicity with in vitro models (IC50 > 30 µM on HEK-293, SH-SY5Y and HepG2 cell lines). Subsequently, binding modes of these ligands are obtained using a model of H3R by docking and molecular dynamics studies, thus determining the importance of the purine ring in enhancing affinity due to the hydrogen bonding of Tyr374 to the N-7 of this heterocycle. Finally, in silico ADME properties are predicted, which indicate a promising future for these molecules in terms of their physical–chemical properties, absorption, oral bioavailability and penetration in the CNS. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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23 pages, 12180 KiB  
Article
Discovery of Nitro-azolo[1,5-a]pyrimidines with Anti-Inflammatory and Protective Activity against LPS-Induced Acute Lung Injury
by Alexander Spasov, Vadim Kosolapov, Denis Babkov, Vladlen Klochkov, Elena Sokolova, Mikhail Miroshnikov, Alexander Borisov, Yulia Velikorodnaya, Alexey Smirnov, Konstantin Savateev, Victor Fedotov, Svetlana Kotovskaya and Vladimir Rusinov
Pharmaceuticals 2022, 15(5), 537; https://doi.org/10.3390/ph15050537 - 27 Apr 2022
Cited by 4 | Viewed by 3262
Abstract
Acute lung injury remains a challenging clinical condition, necessitating the development of novel, safe and efficient treatments. The prevention of macrophage M1-polarization is a viable venue to tackle excessive inflammation. We performed a phenotypic screening campaign to identify azolopyrimidine compounds that effectively inhibit [...] Read more.
Acute lung injury remains a challenging clinical condition, necessitating the development of novel, safe and efficient treatments. The prevention of macrophage M1-polarization is a viable venue to tackle excessive inflammation. We performed a phenotypic screening campaign to identify azolopyrimidine compounds that effectively inhibit LPS-induced NO synthesis and interleukin 6 (IL-6) secretion. We identified lead compound 9g that inhibits IL-6 secretion with IC50 of 3.72 µM without apparent cytotoxicity and with minimal suppression of macrophage phagocytosis in contrast to dexamethasone. In a mouse model of LPS-induced acute lung injury, 30 mg/kg i.p. 9g ameliorated anxiety-like behavior, inhibited IL-6 release, and limited neutrophil infiltration and pulmonary edema. A histological study confirmed the protective activity of 9g. Treatment with compound 9g prevented the migration of CD68+ macrophages and the incidence of hemorrhage. Hence, we have identified a promising pharmacological approach for the treatment of acute lung injury that may hold promise for the development of novel drugs against cytokine-mediated complications of bacterial and viral infections. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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19 pages, 6508 KiB  
Article
Synthesis and Antiproliferative Activity of Novel Imipridone–Ferrocene Hybrids with Triazole and Alkyne Linkers
by Tamás Czuczi, József Murányi, Péter Bárány, István Móra, Adina Borbély, Miklós Csala and Antal Csámpai
Pharmaceuticals 2022, 15(4), 468; https://doi.org/10.3390/ph15040468 - 12 Apr 2022
Cited by 2 | Viewed by 3114
Abstract
Imipridones, including ONC201, ONC206 and ONC212 (which are emblematic members of this class of compounds developed by Oncoceutics) constitute a novel class of anticancer agents, with promising results in clinical trials. With the aim of increasing the ROS (reactive oxygen species) responsivity of [...] Read more.
Imipridones, including ONC201, ONC206 and ONC212 (which are emblematic members of this class of compounds developed by Oncoceutics) constitute a novel class of anticancer agents, with promising results in clinical trials. With the aim of increasing the ROS (reactive oxygen species) responsivity of the synthesized molecules, a set of novel ferrocene–imipridone hybrids were designed and synthesized. Our strategy was motivated by the documented interplay between the imipridone-triggered activation of TRAIL (the tumor necrosis factor-related apoptosis-inducing ligand) and mitochondrial ClpP (Caseinolytic protease P) and the ROS-mediated effect of ferrocene-containing compounds. In order to obtain novel hybrids with multitarget characters, the ferrocene moiety was tethered to the imipridone scaffold through ethynylene and 1,2,3-triazolyl linkers by using Sonogashira coupling of Cu(I)- and Ru(II)-catalyzed azide–alkyne cycloadditions. The biological activities of the new hybrids were examined by using in vitro cell viability assays on four malignant cell lines (PANC-1, A2058, EBC-1 and Fadu), along with colony formation assays on the most resistant PANC-1 cell line. Several hybrids caused a significantly greater drop in the cell viability compared to ONC201, and two of them completely overcame the resistance, with IC50 values comparable to those produced by ONC201. The two most potent hybrids, but not ONC201, induced apoptosis/necrosis in PANC-1 and A2058 cells after 24 h of treatment. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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26 pages, 7439 KiB  
Article
Investigation of Direct and Retro Chromone-2-Carboxamides Based Analogs of Pseudomonas aeruginosa Quorum Sensing Signal as New Anti-Biofilm Agents
by Jeanne Trognon, Gonzalo Vera, Maya Rima, Jean-Luc Stigliani, Laurent Amielet, Salomé El Hage, Barbora Lajoie, Christine Roques and Fatima El Garah
Pharmaceuticals 2022, 15(4), 417; https://doi.org/10.3390/ph15040417 - 29 Mar 2022
Cited by 12 | Viewed by 2720
Abstract
Biofilm formation is considered a major cause of therapeutic failure because bacteria in biofilms have higher protection against antimicrobials. Thus, biofilm-related infections are extremely challenging to treat and pose major concerns for public health, along with huge economic impacts. Pseudomonas aeruginosa, in [...] Read more.
Biofilm formation is considered a major cause of therapeutic failure because bacteria in biofilms have higher protection against antimicrobials. Thus, biofilm-related infections are extremely challenging to treat and pose major concerns for public health, along with huge economic impacts. Pseudomonas aeruginosa, in particular, is a “critical priority” pathogen, responsible for severe infections, especially in cystic fibrosis patients because of its capacity to form resistant biofilms. Therefore, new therapeutic approaches are needed to complete the pipeline of molecules offering new targets and modes of action. Biofilm formation is mainly controlled by Quorum Sensing (QS), a communication system based on signaling molecules. In the present study, we employed a molecular docking approach (Autodock Vina) to assess two series of chromones-based compounds as possible ligands for PqsR, a LuxR-type receptor. Most compounds showed good predicted affinities for PqsR, higher than the PQS native ligand. Encouraged by these docking results, we synthesized a library of 34 direct and 25 retro chromone carboxamides using two optimized routes from 2-chromone carboxylic acid as starting material for both series. We evaluated the synthesized carboxamides for their ability to inhibit the biofilm formation of P. aeruginosa in vitro. Overall, results showed several chromone 2-carboxamides of the retro series are potent inhibitors of the formation of P. aeruginosa biofilms (16/25 compound with % inhibition ≥ 50% at 50 μM), without cytotoxicity on Vero cells (IC50 > 1.0 mM). The 2,4-dinitro-N-(4-oxo-4H-chromen-2-yl) benzamide (6n) was the most promising antibiofilm compound, with potential for hit to lead optimization. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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18 pages, 4520 KiB  
Article
Design, Synthesis, and Cytotoxicity and Topoisomerase I/IIα Inhibition Activity of Pyrazolo[4,3-f]quinoline Derivatives
by Chhabi Lal Chaudhary, Seungyun Ko, Chaerim Lee, Yerin Kim, Chanhyun Jung, Soonsil Hyun, Youngjoo Kwon, Jong-Soon Kang, Jae-Kyung Jung and Heesoon Lee
Pharmaceuticals 2022, 15(4), 399; https://doi.org/10.3390/ph15040399 - 24 Mar 2022
Cited by 3 | Viewed by 2432
Abstract
With the several targets of cancer treatment, inhibition of DNA topoisomerase activity is one of the well-known focuses in cancer chemotherapy. Here, we describe the design and synthesis of a novel series of pyrazolo[4,3-f]quinolines with potential anticancer/topoisomerase inhibition activity. Forty newly [...] Read more.
With the several targets of cancer treatment, inhibition of DNA topoisomerase activity is one of the well-known focuses in cancer chemotherapy. Here, we describe the design and synthesis of a novel series of pyrazolo[4,3-f]quinolines with potential anticancer/topoisomerase inhibition activity. Forty newly designed pyrazolo[4,3-f]quinoline derivatives were synthesized via inverse imino Diels–Alder reaction. The antiproliferative activity of the synthesized derivatives was initially measured in the human NUGC-3 cancer cell line. Then, the selected compounds 1B, 1C, 1M, 2A, 2D, 2E, 2F, and 2R with higher activity among tested compounds were screened against six cancer cell lines, including ACHN, HCT-15, MM231, NCI-H23, NUGC-3, and PC-3. The results demonstrated that the compounds 1M, 2E, and 2P were most effective in all cancer cell lines exhibiting GI50 below 8 µM. Among them, 2E showed an equivalent inhibition pattern of topoisomerase IIα activity to that of etoposide, positive control at a 100 µM dose. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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27 pages, 24015 KiB  
Article
One-Pot Synthesis and Molecular Modeling Studies of New Bioactive Spiro-Oxindoles Based on Uracil Derivatives as SARS-CoV-2 Inhibitors Targeting RNA Polymerase and Spike Glycoprotein
by Samar A. El-Kalyoubi, Ahmed Ragab, Ola A. Abu Ali, Yousry A. Ammar, Mohamed G. Seadawy, Aya Ahmed and Eman A. Fayed
Pharmaceuticals 2022, 15(3), 376; https://doi.org/10.3390/ph15030376 - 20 Mar 2022
Cited by 41 | Viewed by 3087
Abstract
The first outbreak in Wuhan, China, in December 2019 was reported about severe acute coronaviral syndrome 2 (SARS-CoV-2). The global coronavirus disease 2019 (COVID-19) pandemic in 2020 resulted in an extremely high potential for dissemination. No drugs are validated in large-scale studies for [...] Read more.
The first outbreak in Wuhan, China, in December 2019 was reported about severe acute coronaviral syndrome 2 (SARS-CoV-2). The global coronavirus disease 2019 (COVID-19) pandemic in 2020 resulted in an extremely high potential for dissemination. No drugs are validated in large-scale studies for significant effectiveness in the clinical treatment of COVID-19 patients, despite the worsening trends of COVID-19. This study aims to design a simple and efficient cyclo-condensation reaction of 6-aminouracil derivatives 2ae and isatin derivatives 1ac to synthesize spiro-oxindoles 3ad, 4ae, and 5ae. All compounds were tested in vitro against the SARS-CoV-2. Four spiro[indoline-3,5′-pyrido[2,3-d:6,5-d’]dipyrimidine derivatives 3a, 4b, 4d, and 4e showed high activities against the SARS-CoV-2 in plaque reduction assay and were subjected to further RNA-dependent-RNA-polymerase (RdRp) and spike glycoprotein inhibition assay investigations. The four compounds exhibited potent inhibitory activity ranging from 40.23 ± 0.09 to 44.90 ± 0.08 nM and 40.27 ± 0.17 to 44.83 ± 0.16 nM, respectively, when compared with chloroquine as a reference standard, which showed 45 ± 0.02 and 45 ± 0.06 nM against RdRp and spike glycoprotein, respectively. The computational study involving the docking studies of the binding mode inside two proteins ((RdRp) (PDB: 6m71), and (SGp) (PDB: 6VXX)) and geometrical optimization used to generate some molecular parameters were performed for the most active hybrids. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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23 pages, 10217 KiB  
Article
Design, Molecular Docking, Synthesis, Anticancer and Anti-Hyperglycemic Assessments of Thiazolidine-2,4-diones Bearing Sulfonylthiourea Moieties as Potent VEGFR-2 Inhibitors and PPARγ Agonists
by Mohamed A. Abdelgawad, Khaled El-Adl, Sanadelaslam S. A. El-Hddad, Mostafa M. Elhady, Nashwa M. Saleh, Mohamed M. Khalifa, Fathalla Khedr, Mohamed Alswah, AbdElAziz A. Nayl, Mohammed M. Ghoneim and Nour E. A. Abd El-Sattar
Pharmaceuticals 2022, 15(2), 226; https://doi.org/10.3390/ph15020226 - 14 Feb 2022
Cited by 21 | Viewed by 2456
Abstract
Newly designed thiazolidine-2,4-diones 37ac were synthesized, and their anticancer activities were screened against three cancer lines. They showed potent activities against HepG2 compared to the other HCT116 and MCF-7 tumor cell lines. Compounds 7c and 6c were detected as [...] Read more.
Newly designed thiazolidine-2,4-diones 37ac were synthesized, and their anticancer activities were screened against three cancer lines. They showed potent activities against HepG2 compared to the other HCT116 and MCF-7 tumor cell lines. Compounds 7c and 6c were detected as highly effective derivatives against MCF-7 (IC50 = 7.78 and 8.15 µM), HCT116 (IC50 = 5.77 and 7.11 µM) and HepG2 (IC50 = 8.82 and 8.99 µM). The highly effective derivatives 6ac and 7ac were tested against VERO normal cell lines. All derivatives were evaluated for their VEGFR-2 inhibitory actions and demonstrated high to low activities, with IC50 values varying from 0.08 to 0.93 µM. Moreover, derivatives 5ac, 6ac and 7ac were assessed to verify their in vitro binding affinities to PPARγ and insulin-secreting activities. Finally, docking studies were performed to explore their affinities and binding modes toward both VEGFR-2 and PPARγ receptors. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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22 pages, 9054 KiB  
Article
Identification of Cyclic Sulfonamides with an N-Arylacetamide Group as α-Glucosidase and α-Amylase Inhibitors: Biological Evaluation and Molecular Modeling
by Furqan Ahmad Saddique, Matloob Ahmad, Usman Ali Ashfaq, Muhammad Muddassar, Sadia Sultan and Magdi E. A. Zaki
Pharmaceuticals 2022, 15(1), 106; https://doi.org/10.3390/ph15010106 - 17 Jan 2022
Cited by 14 | Viewed by 2865
Abstract
Diabetes mellitus (DM), a complicated metabolic disorder, is due to insensitivity to insulin function or reduction in insulin secretion, which results in postprandial hyperglycemia. α-Glucosidase inhibitors (AGIs) and α-amylase inhibitors (AAIs) block the function of digestive enzymes, which delays the carbohydrate hydrolysis process [...] Read more.
Diabetes mellitus (DM), a complicated metabolic disorder, is due to insensitivity to insulin function or reduction in insulin secretion, which results in postprandial hyperglycemia. α-Glucosidase inhibitors (AGIs) and α-amylase inhibitors (AAIs) block the function of digestive enzymes, which delays the carbohydrate hydrolysis process and ultimately helps to control the postprandial hyperglycemia. Diversified 2-(3-(3-methoxybenzoyl)-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-arylacetamides were synthesized and evaluated for their in vitro inhibitory potential against α-glucosidase and α-amylase enzymes. The compounds with chloro, bromo and methyl substituents demonstrated good inhibition of α-glucosidase enzymes having IC50 values in the range of 25.88–46.25 μM, which are less than the standard drug, acarbose (IC50 = 58.8 μM). Similarly, some derivatives having chloro, bromo and nitro substituents were observed potent inhibitors of α-amylase enzyme, with IC50 values of 7.52 to 15.06 μM, lower than acarbose (IC50 = 17.0 μM). In addition, the most potent compound, N-(4-bromophenyl)-2-(4-hydroxy-3-(3-methoxybenzoyl)-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)acetamide (12i), was found to be a non-competitive and competitive inhibitor of α-glucosidase and α-amylase enzymes, respectively, during kinetic studies. The molecular docking studies provided the binding modes of active compounds and the molecular dynamics simulation studies of compound 12i in complex with α-amylase also showed that the compound is binding in a fashion similar to that predicted by molecular docking studies. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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15 pages, 3675 KiB  
Article
Azacitidine Omega-3 Self-Assemblies: Synthesis, Characterization, and Potent Applications for Myelodysplastic Syndromes
by Milad Baroud, Elise Lepeltier, Yolla El-Makhour, Nolwenn Lautram, Jerome Bejaud, Sylvain Thepot and Olivier Duval
Pharmaceuticals 2021, 14(12), 1317; https://doi.org/10.3390/ph14121317 - 17 Dec 2021
Cited by 1 | Viewed by 2962
Abstract
5-Azacitidine, a cytidine analogue used as a hypomethylating agent, is one of the main drugs for the treatment of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) in the elderly. However, after administration, it exhibits several limitations, including restricted diffusion and cellular internalization [...] Read more.
5-Azacitidine, a cytidine analogue used as a hypomethylating agent, is one of the main drugs for the treatment of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) in the elderly. However, after administration, it exhibits several limitations, including restricted diffusion and cellular internalization due to its hydrophilicity, and a rapid enzymatic degradation by adenosine deaminase. The aim of this study was to improve the drug cell diffusion and protect it from metabolic degradation via the synthesis of amphiphilic prodrugs and their potential self-assembly. Azacitidine was conjugated to two different omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The carboxylic acid group of the omega-3 fatty acids was effectively conjugated to the amine group of the azacitidine base, yielding two amphiphilic prodrugs. Nanoprecipitation of the obtained prodrugs was performed and self-assemblies were successfully obtained for both prodrugs, with a mean diameter of 190 nm, a polydispersity index below 0.2 and a positive zeta potential. The formation of self-assemblies was confirmed using pyrene as a fluorescent dye, and the critical aggregation concentrations were determined: 400 µM for AzaEPA and 688 µM for AzaDHA. Additionally, the stability of the obtained self-assemblies was studied and after 5 days their final stable arrangement was reached. Additionally, cryo-TEM revealed that the self-assemblies attain a multilamellar vesicle supramolecular structure. Moreover, the obtained self-assemblies presented promising cytotoxicity on a leukemia human cell line, having a low IC50 value, comparable to that of free azacitidine. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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17 pages, 217175 KiB  
Article
Expanding the Diversity at the C-4 Position of Pyrido[2,3-d]pyrimidin-7(8H)-ones to Achieve Biological Activity against ZAP-70
by Victor Masip, Ángel Lirio, Albert Sánchez-López, Ana B. Cuenca, Raimon Puig de la Bellacasa, Pau Abrisqueta, Jordi Teixidó, José I. Borrell, Albert Gibert and Roger Estrada-Tejedor
Pharmaceuticals 2021, 14(12), 1311; https://doi.org/10.3390/ph14121311 - 15 Dec 2021
Cited by 1 | Viewed by 2480
Abstract
Pyrido[2,3-d]pyrimidin-7(8H)-ones have attracted widespread interest due to their similarity with nitrogenous bases found in DNA and RNA and their potential applicability as tyrosine kinase inhibitors. Such structures, presenting up to five diversity centers, have allowed the synthesis of a [...] Read more.
Pyrido[2,3-d]pyrimidin-7(8H)-ones have attracted widespread interest due to their similarity with nitrogenous bases found in DNA and RNA and their potential applicability as tyrosine kinase inhibitors. Such structures, presenting up to five diversity centers, have allowed the synthesis of a wide range of differently substituted compounds; however, the diversity at the C4 position has mostly been limited to a few substituents. In this paper, a general synthetic methodology for the synthesis of 4-substituted-2-(phenylamino)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones is described. By using cross-coupling reactions, such as Ullmann, Buchwald–Hartwig, Suzuki–Miyaura, or Sonogashira reactions, catalyzed by Cu or Pd, we were able to describe new potential biologically active compounds. The resulting pyrido[2,3-d]pyrimidin-7(8H)-ones include N-alkyl, N-aryl, O-aryl, S-aryl, aryl, and arylethynyl substituents at C4, which have never been explored in connection with the biological activity of such heterocycles as tyrosine kinase inhibitors, in particular as ZAP-70 inhibitors. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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20 pages, 12040 KiB  
Article
Heterocyclic Cathinones as Inhibitors of Kynurenine Aminotransferase II—Design, Synthesis, and Evaluation
by Michal Maryška, Lucie Svobodová, Wim Dehaen, Martina Hrabinová, Michaela Rumlová, Ondřej Soukup and Martin Kuchař
Pharmaceuticals 2021, 14(12), 1291; https://doi.org/10.3390/ph14121291 - 10 Dec 2021
Cited by 3 | Viewed by 3418
Abstract
Kynurenic acid is a neuroprotective metabolite of tryptophan formed by kynurenine aminotransferase (KAT) catalyzed transformation of kynurenine. However, its high brain levels are associated with cognitive deficit and with the pathophysiology of schizophrenia. Although several classes of KAT inhibitors have been published, the [...] Read more.
Kynurenic acid is a neuroprotective metabolite of tryptophan formed by kynurenine aminotransferase (KAT) catalyzed transformation of kynurenine. However, its high brain levels are associated with cognitive deficit and with the pathophysiology of schizophrenia. Although several classes of KAT inhibitors have been published, the search for new inhibitor chemotypes is crucial for the process of finding suitable clinical candidates. Therefore, we used pharmacophore modeling and molecular docking, which predicted derivatives of heterocyclic amino ketones as new potential irreversible inhibitors of kynurenine aminotransferase II. Thiazole and triazole-based amino ketones were synthesized within a SAR study and their inhibitory activities were evaluated in vitro. The observed activities confirmed our computational model and, moreover, the best compounds showed sub-micromolar inhibitory activity with 2-alaninoyl-5-(4-fluorophenyl)thiazole having IC50 = 0.097 µM. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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20 pages, 6339 KiB  
Article
Hit Identification of a Novel Quinazoline Sulfonamide as a Promising EphB3 Inhibitor: Design, Virtual Combinatorial Library, Synthesis, Biological Evaluation, and Docking Simulation Studies
by Kyeong Lee, Hossam Nada, Hyun Jung Byun, Chang Hoon Lee and Ahmed Elkamhawy
Pharmaceuticals 2021, 14(12), 1247; https://doi.org/10.3390/ph14121247 - 30 Nov 2021
Cited by 9 | Viewed by 2738
Abstract
EphB3 is a major key player in a variety of cellular activities, including cell migration, proliferation, and apoptosis. However, the exact role of EphB3 in cancer remains ambiguous. Accordingly, new EphB3 inhibitors can increase the understanding of the exact roles of the receptor [...] Read more.
EphB3 is a major key player in a variety of cellular activities, including cell migration, proliferation, and apoptosis. However, the exact role of EphB3 in cancer remains ambiguous. Accordingly, new EphB3 inhibitors can increase the understanding of the exact roles of the receptor and may act as promising therapeutic candidates. Herein, a hybrid approach of structure-based design and virtual combinatorial library generated 34 quinazoline sulfonamides as potential selective EphB3 inhibitors. A molecular docking study over EphB3 predicted the binding affinities of the generated library, and the top seven hit compounds (3a and 4af), with GlideScore ≥ −6.20 Kcal/mol, were chosen for further MM-GBSA calculations. Out of the seven top hits, compound 4c showed the highest MM-GBSA binding free energy (−74.13 Kcal/mol). To validate these predicted results, compounds 3a and 4af were synthesized and characterized using NMR, HRMS, and HPLC. The biological evaluation revealed compound 4c as a potent EphB3 inhibitory lead (IC50 = 1.04 µM). The screening of 4c over a mini-panel of kinases consisting of EGFR, Aurora A, Aurora B, CDK2/cyclin A, EphB1, EphB2, EphB4, ERBB2/HER2, and KDR/VEGFR2, showed a promising selective profile against EphB3 isoform. A dose-dependent assay of compound 4c and a molecular docking study over the different forms of EphB provided insights into the elicited biological activities and highlighted reasonable explanations of the selectivity. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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30 pages, 4079 KiB  
Article
Design and Microwave Synthesis of New (5Z) 5-Arylidene-2-thioxo-1,3-thiazolinidin-4-one and (5Z) 2-Amino-5-arylidene-1,3-thiazol-4(5H)-one as New Inhibitors of Protein Kinase DYRK1A
by Khadidja Bourahla, Solène Guihéneuf, Emmanuelle Limanton, Ludovic Paquin, Rémy Le Guével, Thierry Charlier, Mustapha Rahmouni, Emilie Durieu, Olivier Lozach, François Carreaux, Laurent Meijer and Jean-Pierre Bazureau
Pharmaceuticals 2021, 14(11), 1086; https://doi.org/10.3390/ph14111086 - 27 Oct 2021
Cited by 6 | Viewed by 2857
Abstract
Here, we report on the synthesis of libraries of new 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones 3 (twenty-two compounds) and new 2-amino-5-arylidene-1,3-thiazol-4(5H)-ones 5 (twenty-four compounds) with stereo controlled Z-geometry under microwave irradiation. The 46 designed final compounds were tested in order to determine their activity [...] Read more.
Here, we report on the synthesis of libraries of new 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones 3 (twenty-two compounds) and new 2-amino-5-arylidene-1,3-thiazol-4(5H)-ones 5 (twenty-four compounds) with stereo controlled Z-geometry under microwave irradiation. The 46 designed final compounds were tested in order to determine their activity against four representative protein kinases (DYR1A, CK1, CDK5/p25, and GSK3α/β). Among these 1,3-thiazolidin-4-ones, the molecules (5Z) 5-(4-hydroxybenzylidene)-2-thioxo-1,3-thiazolidin-4-one 3e (IC50 0.028 μM) and (5Z)-5-benzo[1,3]dioxol-5-ylmethylene-2-(pyridin-2-yl)amino-1,3-thiazol-4(5H)-one 5s (IC50 0.033 μM) were identified as lead compounds and as new nanomolar DYRK1A inhibitors. Some of these compounds in the two libraries have been also evaluated for their in vitro inhibition of cell proliferation (Huh7 D12, Caco2, MDA-MB 231, HCT 116, PC3, and NCI-H2 tumor cell lines). These results will enable us to use the 1,3-thiazolidin-4-one core as pharmacophores to develop potent treatment for neurological or oncological disorders in which DYRK1A is fully involved. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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18 pages, 9238 KiB  
Article
Pioglitazone Is a Mild Carrier-Dependent Uncoupler of Oxidative Phosphorylation and a Modulator of Mitochondrial Permeability Transition
by Ekaterina S. Kharechkina, Anna B. Nikiforova, Konstantin N. Belosludtsev, Tatyana I. Rokitskaya, Yuri N. Antonenko and Alexey G. Kruglov
Pharmaceuticals 2021, 14(10), 1045; https://doi.org/10.3390/ph14101045 - 14 Oct 2021
Cited by 6 | Viewed by 2855
Abstract
Pioglitazone (PIO) is an insulin-sensitizing antidiabetic drug, which normalizes glucose and lipid metabolism but may provoke heart and liver failure and chronic kidney diseases. Both therapeutic and adverse effects of PIO can be accomplished through mitochondrial targets. Here, we explored the capability of [...] Read more.
Pioglitazone (PIO) is an insulin-sensitizing antidiabetic drug, which normalizes glucose and lipid metabolism but may provoke heart and liver failure and chronic kidney diseases. Both therapeutic and adverse effects of PIO can be accomplished through mitochondrial targets. Here, we explored the capability of PIO to modulate the mitochondrial membrane potential (ΔΨm) and the permeability transition pore (mPTP) opening in different models in vitro. ΔΨm was measured using tetraphenylphosphonium and the fluorescent dye rhodamine 123. The coupling of oxidative phosphorylation was estimated polarographically. The transport of ions and solutes across membranes was registered by potentiometric and spectral techniques. We found that PIO decreased ΔΨm in isolated mitochondria and intact thymocytes and the efficiency of ADP phosphorylation, particularly after the addition of Ca2+. The presence of the cytosolic fraction mitigated mitochondrial depolarization but made it sustained. Carboxyatractyloside diminished the PIO-dependent depolarization. PIO activated proton transport in deenergized mitochondria but not in artificial phospholipid vesicles. PIO had no effect on K+ and Ca2+ inward transport but drastically decreased the mitochondrial Ca2+-retention capacity and protective effects of adenine nucleotides against mPTP opening. Thus, PIO is a mild, partly ATP/ADP-translocase-dependent, uncoupler and a modulator of ATP production and mPTP sensitivity to Ca2+ and adenine nucleotides. These properties contribute to both therapeutic and adverse effects of PIO. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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22 pages, 2236 KiB  
Article
Synthesis and Biological Evaluation of (S)-2-(Substituted arylmethyl)-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide Analogs and Their Synergistic Effect against PTEN-Deficient MDA-MB-468 Cells
by Ye-Mi Kwon, Sou Hyun Kim, Young-Suk Jung and Jae-Hwan Kwak
Pharmaceuticals 2021, 14(10), 974; https://doi.org/10.3390/ph14100974 - 25 Sep 2021
Cited by 2 | Viewed by 1934
Abstract
A series of twenty-six compounds of furfuryl or benzyl tetrahydropyrazino[1,2-a]indole analogs were synthesized and evaluated for cytotoxic activity against the estrogen receptor (ER)-positive breast cancer cell line (MCF-7) and the epidermal growth factor receptor (EGFR) over-expressed triple-negative breast cancer cell line [...] Read more.
A series of twenty-six compounds of furfuryl or benzyl tetrahydropyrazino[1,2-a]indole analogs were synthesized and evaluated for cytotoxic activity against the estrogen receptor (ER)-positive breast cancer cell line (MCF-7) and the epidermal growth factor receptor (EGFR) over-expressed triple-negative breast cancer cell line (MDA-MB-468). Among them, compounds 2b, 2f and 2i showed more potent activity and selectivity against MDA-MB-468 cells than gefitinib, as an EGFR- tyrosine kinase inhibitor. In addition, it was confirmed by means of isobologram analysis of combinational treatment with gefitinib that they have a synergistic effect, especially compounds 2b and 2f, which inhibit Akt T308 phosphorylation. Moreover, it was confirmed that 2-benzyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide analogs (2b, 2f, and Ref 2) tend to selectively inhibit PI3Kβ, which is involved in the phosphorylation of Akt. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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15 pages, 4234 KiB  
Article
Pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5-amines as Potential Cytotoxic Agents against Human Neuroblastoma
by Zahira Tber, Mohammed Loubidi, Jabrane Jouha, Ismail Hdoufane, Mümin Alper Erdogan, Luciano Saso, Güliz Armagan and Sabine Berteina-Raboin
Pharmaceuticals 2021, 14(8), 750; https://doi.org/10.3390/ph14080750 - 30 Jul 2021
Viewed by 2369
Abstract
We report herein the evaluation of various pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5-amines as potential cytotoxic agents. These molecules were obtained by developing the multicomponent Groebke–Blackburn–Bienaymé reaction to yield various pyrido[2′,1′:2,3]imidazo[4,5-c]quinolines which are isosteres of ellipticine whose biological activities are well established. To evaluate the anticancer [...] Read more.
We report herein the evaluation of various pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5-amines as potential cytotoxic agents. These molecules were obtained by developing the multicomponent Groebke–Blackburn–Bienaymé reaction to yield various pyrido[2′,1′:2,3]imidazo[4,5-c]quinolines which are isosteres of ellipticine whose biological activities are well established. To evaluate the anticancer potential of these pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5-amine derivatives in the human neuroblastoma cell line, the cytotoxicity was examined using the WST-1 assay after 72 h drug exposure. A clonogenic assay was used to assess the ability of treated cells to proliferate and form colonies. Protein expressions (Bax, bcl-2, cleaved caspase-3, cleaved PARP-1) were analyzed using Western blotting. The colony number decrease in cells was 50.54%, 37.88% and 27.12% following exposure to compounds 2d, 2g and 4b respectively at 10 μM. We also show that treating the neuroblastoma cell line with these compounds resulted in a significant alteration in caspase-3 and PARP-1 cleavage. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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24 pages, 1959 KiB  
Article
2-Phenoxy-3-Trichloromethylquinoxalines Are Antiplasmodial Derivatives with Activity against the Apicoplast of Plasmodium falciparum
by Dyhia Amrane, Christophe-Sébastien Arnold, Sébastien Hutter, Julen Sanz-Serrano, Miguel Collia, Amaya Azqueta, Lucie Paloque, Anita Cohen, Nadia Amanzougaghene, Shahin Tajeri, Jean-François Franetich, Dominique Mazier, Françoise Benoit-Vical, Pierre Verhaeghe, Nadine Azas, Patrice Vanelle, Cyrille Botté and Nicolas Primas
Pharmaceuticals 2021, 14(8), 724; https://doi.org/10.3390/ph14080724 - 26 Jul 2021
Cited by 5 | Viewed by 3386
Abstract
The malaria parasite harbors a relict plastid called the apicoplast. Although not photosynthetic, the apicoplast retains unusual, non-mammalian metabolic pathways that are essential to the parasite, opening up a new perspective for the development of novel antimalarials which display a new mechanism of [...] Read more.
The malaria parasite harbors a relict plastid called the apicoplast. Although not photosynthetic, the apicoplast retains unusual, non-mammalian metabolic pathways that are essential to the parasite, opening up a new perspective for the development of novel antimalarials which display a new mechanism of action. Based on the previous antiplasmodial hit-molecules identified in the 2-trichloromethylquinoxaline series, we report herein a structure–activity relationship (SAR) study at position two of the quinoxaline ring by synthesizing 20 new compounds. The biological evaluation highlighted a hit compound (3i) with a potent PfK1 EC50 value of 0.2 µM and a HepG2 CC50 value of 32 µM (Selectivity index = 160). Nitro-containing (3i) was not genotoxic, both in the Ames test and in vitro comet assay. Activity cliffs were observed when the 2-CCl3 group was replaced, showing that it played a key role in the antiplasmodial activity. Investigation of the mechanism of action showed that 3i presents a drug response by targeting the apicoplast and a quick-killing mechanism acting on another target site. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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17 pages, 1636 KiB  
Article
Design, Synthesis, and Antibacterial Screening of Some Novel Heteroaryl-Based Ciprofloxacin Derivatives as DNA Gyrase and Topoisomerase IV Inhibitors
by Lamya H. Al-Wahaibi, Amer A. Amer, Adel A. Marzouk, Hesham A. M. Gomaa, Bahaa G. M. Youssif and Antar A. Abdelhamid
Pharmaceuticals 2021, 14(5), 399; https://doi.org/10.3390/ph14050399 - 22 Apr 2021
Cited by 22 | Viewed by 2847
Abstract
A novel series of ciprofloxacin hybrids comprising various heterocycle derivatives has been synthesized and structurally elucidated using 1H NMR, 13C NMR, and elementary analyses. Using ciprofloxacin as a reference, compounds 1–21 were screened in vitro against Gram-positive bacterial strains such as [...] Read more.
A novel series of ciprofloxacin hybrids comprising various heterocycle derivatives has been synthesized and structurally elucidated using 1H NMR, 13C NMR, and elementary analyses. Using ciprofloxacin as a reference, compounds 1–21 were screened in vitro against Gram-positive bacterial strains such as Staphylococcus aureus and Bacillus subtilis and Gram-negative strains such as Escherichia coli and Pseudomonas aeruginosa. As a result, many of the compounds examined had antibacterial activity equivalent to ciprofloxacin against test bacteria. Compounds 2–6, oxadiazole derivatives, were found to have antibacterial activity that was 88 to 120% that of ciprofloxacin against Gram-positive and Gram-negative bacteria. The findings showed that none of the compounds tested had antifungal activity against Aspergillus flavus, but did have poor activity against Candida albicans, ranging from 23% to 33% of fluconazole, with compound 3 being the most active (33% of fluconazole). The most potent compounds, 3, 4, 5, and 6, displayed an IC50 of 86, 42, 92, and 180 nM against E. coli DNA gyrase, respectively (novobiocin, IC50 = 170 nM). Compounds 4, 5, and 6 showed IC50 values (1.47, 6.80, and 8.92 µM, respectively) against E. coli topo IV in comparison to novobiocin (IC50 = 11 µM). Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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24 pages, 2798 KiB  
Article
Novel Potent and Selective DPP-4 Inhibitors: Design, Synthesis and Molecular Docking Study of Dihydropyrimidine Phthalimide Hybrids
by Ahmed A. E. Mourad, Ahmed E. Khodir, Sameh Saber and Mai A. E. Mourad
Pharmaceuticals 2021, 14(2), 144; https://doi.org/10.3390/ph14020144 - 11 Feb 2021
Cited by 24 | Viewed by 3549
Abstract
Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged as anti-hyperglycemic agents that improve glycemic control in type 2 diabetic patients, either as monotherapy or in combination with other antidiabetic drugs. Methods: A novel series of dihydropyrimidine phthalimide hybrids was synthesized and evaluated for their [...] Read more.
Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged as anti-hyperglycemic agents that improve glycemic control in type 2 diabetic patients, either as monotherapy or in combination with other antidiabetic drugs. Methods: A novel series of dihydropyrimidine phthalimide hybrids was synthesized and evaluated for their in vitro and in vivo DPP-4 inhibition activity and selectivity using alogliptin as reference. Oral glucose tolerance test was assessed in type 2 diabetic rats after chronic treatment with the synthesized hybrids ± metformin. Cytotoxicity and antioxidant assays were performed. Additionally, molecular docking study with DPP-4 and structure activity relationship of the novel hybrids were also studied. Results: Among the synthesized hybrids, 10g, 10i, 10e, 10d and 10b had stronger in vitro DPP-4 inhibitory activity than alogliptin. Moreover, an in vivo DPP-4 inhibition assay revealed that 10g and 10i have the strongest and the most extended blood DPP-4 inhibitory activity compared to alogliptin. In type 2 diabetic rats, hybrids 10g, 10i and 10e exhibited better glycemic control than alogliptin, an effect that further supported by metformin combination. Finally, 10j, 10e, 10h and 10d had the highest radical scavenging activity in DPPH assay. Conclusions: Hybrids 10g, 10i and 10e are potent DPP-4 inhibitors which may be beneficial for T2DM treatment. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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Review

Jump to: Research

35 pages, 10746 KiB  
Review
Isoxazole/Isoxazoline Skeleton in the Structural Modification of Natural Products: A Review
by Xiyue Wang, Qingyun Hu, Hui Tang and Xinhui Pan
Pharmaceuticals 2023, 16(2), 228; https://doi.org/10.3390/ph16020228 - 2 Feb 2023
Cited by 12 | Viewed by 3399
Abstract
Isoxazoles and isoxazolines are five-membered heterocyclic molecules containing nitrogen and oxygen. Isoxazole and isoxazoline are the most popular heterocyclic compounds for developing novel drug candidates. Over 80 molecules with a broad range of bioactivities, including antitumor, antibacterial, anti-inflammatory, antidiabetic, cardiovascular, and other activities, [...] Read more.
Isoxazoles and isoxazolines are five-membered heterocyclic molecules containing nitrogen and oxygen. Isoxazole and isoxazoline are the most popular heterocyclic compounds for developing novel drug candidates. Over 80 molecules with a broad range of bioactivities, including antitumor, antibacterial, anti-inflammatory, antidiabetic, cardiovascular, and other activities, were reviewed. A review of recent studies on the use of isoxazoles and isoxazolines moiety derivative activities for natural products is presented here, focusing on the parameters that affect the bioactivity of these compounds. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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18 pages, 3838 KiB  
Review
A Review of Synthetic Access to Therapeutic Compounds Extracted from Psilocybe
by Raphaël Serreau, Ammar Amirouche, Amine Benyamina and Sabine Berteina-Raboin
Pharmaceuticals 2023, 16(1), 40; https://doi.org/10.3390/ph16010040 - 28 Dec 2022
Cited by 1 | Viewed by 4519
Abstract
Psychedelics are used for various pathologies of the central nervous system and are currently the subject of much research, some of which relates to the compounds contained in various Psilocybe-type hallucinogenic mushrooms. It is difficult, however, to obtain and purify sufficient quantities [...] Read more.
Psychedelics are used for various pathologies of the central nervous system and are currently the subject of much research, some of which relates to the compounds contained in various Psilocybe-type hallucinogenic mushrooms. It is difficult, however, to obtain and purify sufficient quantities of these compounds from fungi to carry out biological studies, hence the need to develop simple and efficient synthetic routes. We review here the various syntheses used to obtain these molecules, focusing first on the classic historical syntheses, then the use of more recent metallo-catalyzed couplings and finally the known biocatalytic methods for obtaining these molecules. Other access routes are certainly possible and should be the subject of future research given the therapeutic interest of these compounds. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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27 pages, 17084 KiB  
Review
Review on the Synthesis and Therapeutic Potential of Pyrido[2,3-d], [3,2-d], [3,4-d] and [4,3-d]pyrimidine Derivatives
by Joana F. Campos, Thierry Besson and Sabine Berteina-Raboin
Pharmaceuticals 2022, 15(3), 352; https://doi.org/10.3390/ph15030352 - 14 Mar 2022
Cited by 13 | Viewed by 3932
Abstract
The objective of this review is to list the structures composed of a pyridopyrimidine moiety which have shown a therapeutic interest or have already been approved for use as therapeutics. We consider all the synthetic protocols to prepare these pyridopyrimidine derivatives. The review [...] Read more.
The objective of this review is to list the structures composed of a pyridopyrimidine moiety which have shown a therapeutic interest or have already been approved for use as therapeutics. We consider all the synthetic protocols to prepare these pyridopyrimidine derivatives. The review is organized into four sections, successively pyrido[2,3-d]pyrimidines, pyrido[3,4-d]pyrimidines, pyrido[4,3-d]pyrimidines and pyrido[3,2-d]pyrimidines. For each compound we present the biological activity and the synthetic route reported. To produce this manuscript, the bibliographic research was done using Reaxys and Scifinder for each kind of pyridopyrimidine. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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58 pages, 77792 KiB  
Review
Thienopyrimidine: A Promising Scaffold to Access Anti-Infective Agents
by Prisca Lagardère, Cyril Fersing, Nicolas Masurier and Vincent Lisowski
Pharmaceuticals 2022, 15(1), 35; https://doi.org/10.3390/ph15010035 - 27 Dec 2021
Cited by 16 | Viewed by 4366
Abstract
Thienopyrimidines are widely represented in the literature, mainly due to their structural relationship with purine base such as adenine and guanine. This current review presents three isomers—thieno[2,3-d]pyrimidines, thieno[3,2-d]pyrimidines and thieno[3,4-d]pyrimidines—and their anti-infective properties. Broad-spectrum thienopyrimidines with biological [...] Read more.
Thienopyrimidines are widely represented in the literature, mainly due to their structural relationship with purine base such as adenine and guanine. This current review presents three isomers—thieno[2,3-d]pyrimidines, thieno[3,2-d]pyrimidines and thieno[3,4-d]pyrimidines—and their anti-infective properties. Broad-spectrum thienopyrimidines with biological properties such as antibacterial, antifungal, antiparasitic and antiviral inspired us to analyze and compile their structure–activity relationship (SAR) and classify their synthetic pathways. This review explains the main access route to synthesize thienopyrimidines from thiophene derivatives or from pyrimidine analogs. In addition, SAR study and promising anti-infective activity of these scaffolds are summarized in figures and explanatory diagrams. Ligand–receptor interactions were modeled when the biological target was identified and the crystal structure was solved. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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15 pages, 2192 KiB  
Review
Diversity-Oriented Synthesis: Amino Acetophenones as Building Blocks for the Synthesis of Natural Product Analogs
by Mathias Eymery, Viet-Khoa Tran-Nguyen and Ahcène Boumendjel
Pharmaceuticals 2021, 14(11), 1127; https://doi.org/10.3390/ph14111127 - 5 Nov 2021
Cited by 4 | Viewed by 2470
Abstract
Diversity-Oriented Synthesis (DOS) represents a strategy to obtain molecule libraries with diverse structural features starting from one common compound in limited steps of synthesis. During the last two decades, DOS has become an unmissable strategy in organic synthesis and is fully integrated in [...] Read more.
Diversity-Oriented Synthesis (DOS) represents a strategy to obtain molecule libraries with diverse structural features starting from one common compound in limited steps of synthesis. During the last two decades, DOS has become an unmissable strategy in organic synthesis and is fully integrated in various drug discovery processes. On the other hand, natural products with multiple relevant pharmacological properties have been extensively investigated as scaffolds for ligand-based drug design. In this article, we report the amino dimethoxyacetophenones that can be easily synthesized and scaled up from the commercially available 3,5-dimethoxyaniline as valuable starting blocks for the DOS of natural product analogs. More focus is placed on the synthesis of analogs of flavones, coumarins, azocanes, chalcones, and aurones, which are frequently studied as lead compounds in drug discovery. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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15 pages, 3274 KiB  
Review
1,6-Naphthyridin-2(1H)-ones: Synthesis and Biomedical Applications
by Juan Marcos Oliveras, Raimon Puig de la Bellacasa, Roger Estrada-Tejedor, Jordi Teixidó and José I. Borrell
Pharmaceuticals 2021, 14(10), 1029; https://doi.org/10.3390/ph14101029 - 9 Oct 2021
Cited by 3 | Viewed by 2237
Abstract
Naphthyridines, also known as diazanaphthalenes, are a group of heterocyclic compounds that include six isomeric bicyclic systems containing two pyridine rings. 1,6-Naphthyridines are one of the members of such a family capable of providing ligands for several receptors in the body. Among such [...] Read more.
Naphthyridines, also known as diazanaphthalenes, are a group of heterocyclic compounds that include six isomeric bicyclic systems containing two pyridine rings. 1,6-Naphthyridines are one of the members of such a family capable of providing ligands for several receptors in the body. Among such structures, 1,6-naphthyridin-2(1H)-ones (7) are a subfamily that includes more than 17,000 compounds (with a single or double bond between C3 and C4) included in more than 1000 references (most of them patents). This review will cover the analysis of the diversity of the substituents present at positions N1, C3, C4, C5, C7, and C8 of 1,6-naphthyridin-2(1H)-ones, the synthetic methods used for their synthesis (both starting from a preformed pyridine or pyridone ring), and the biomedical applications of such compounds. Full article
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
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