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27 pages, 2725 KiB

Open AccessArticle

Synthesis, Antimicrobial and Antibiofilm Activities, and Molecular Docking Investigations of 2-(1H-Indol-3-yl)-1H-benzo[d]imidazole Derivatives

by Elena Y. Mendogralo, Larisa Y. Nesterova, Ekaterina R. Nasibullina, Roman O. Shcherbakov, Danil A. Myasnikov, Alexander G. Tkachenko, Roman Y. Sidorov and Maxim G. Uchuskin

Molecules 2023, 28(20), 7095; https://doi.org/10.3390/molecules28207095 - 14 Oct 2023

Cited by 1 | Viewed by 1358

Abstract

The treatment of many bacterial and fungal infections remains a problem due to increasing antibiotic resistance and biofilm formation by pathogens. In the present article, a methodology for the chemoselective synthesis of 2-(1H-indol-3-yl)-1H-benzo[d]imidazole derivatives is presented. We [...] Read more.

The treatment of many bacterial and fungal infections remains a problem due to increasing antibiotic resistance and biofilm formation by pathogens. In the present article, a methodology for the chemoselective synthesis of 2-(1H-indol-3-yl)-1H-benzo[d]imidazole derivatives is presented. We report on the antimicrobial activity of synthesized 2-(1H-indol-3-yl)-1H-benzo[d]imidazoles with significant activity against Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 43300 (MRSA), Mycobacterium smegmatis (mc(2)155/ATCC 700084), and Candida albicans ATCC 10231. High activity against staphylococci was shown by indolylbenzo[d]imidazoles 3ao and 3aq (minimum inhibitory concentration (MIC) < 1 µg/mL) and 3aa and 3ad (MIC 3.9–7.8 µg/mL). A low MIC was demonstrated by 2-(1H-indol-3-yl)-1-methyl-1H-benzo[d]imidazole (3ag) against M. smegmatis and against C. albicans (3.9 µg/mL and 3.9 µg/mL, respectively). 2-(5-Bromo-1H-indol-3-yl)-6,7-dimethyl-1H-benzo[d]imidazole (3aq) showed a low MIC of 3.9 µg/mL against C. albicans. Compounds 3aa, 3ad, 3ao, and 3aq exhibited excellent antibiofilm activity, inhibiting biofilm formation and killing cells in mature biofilms. Molecular docking analysis identified three potential interaction models for the investigated compounds, implicating (p)ppGpp synthetases/hydrolases, FtsZ proteins, or pyruvate kinases in their antibacterial action mechanism. Full article

(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation)

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25 pages, 8632 KiB

Open AccessArticle

Finding a Novel Chalcone–Cinnamic Acid Chimeric Compound with Antiproliferative Activity against MCF-7 Cell Line Using a Free-Wilson Type Approach

by Isis A. Y. Ventura-Salazar, Francisco J. Palacios-Can, Leticia González-Maya, Jessica Nayelli Sánchez-Carranza, Mayra Antunez-Mojica, Rodrigo Said Razo-Hernández and Laura Alvarez

Molecules 2023, 28(14), 5486; https://doi.org/10.3390/molecules28145486 - 18 Jul 2023

Cited by 2 | Viewed by 1342

Abstract

In this work, we carried out the design and synthesis of new chimeric compounds from the natural cytotoxic chalcone 2′,4′-dihydroxychalcone (2′,4′-DHC, A) in combination with cinnamic acids. For this purpose, a descriptive and predictive quantitative structure–activity relationship (QSAR) model was developed to [...] Read more.

In this work, we carried out the design and synthesis of new chimeric compounds from the natural cytotoxic chalcone 2′,4′-dihydroxychalcone (2′,4′-DHC, A) in combination with cinnamic acids. For this purpose, a descriptive and predictive quantitative structure–activity relationship (QSAR) model was developed to study the chimeric compounds’ anti-cancer activities against human breast cancer MCF-7, relying on the presence or absence of structural motifs in the chalcone structure, like in a Free-Wilson approach. For this, we used 207 chalcone derivatives with a great variety of structural modifications over the α and β rings, such as halogens (F, Cl, and Br), heterocyclic rings (piperazine, piperidine, pyridine, etc.), and hydroxyl and methoxy groups. The multilinear equation was obtained by the genetic algorithm technique, using logIC₅₀ as a dependent variable and molecular descriptors (constitutional, topological, functional group count, atom-centered fragments, and molecular properties) as independent variables, with acceptable statistical parameter values (

R^{2}

= 86.93,

Q^{2}

_LMO = 82.578,

Q^{2}

_BOOT = 80.436, and

Q^{2}

_EXT = 80.226), which supports the predictive ability of the model. Considering the aromatic and planar nature of the chalcone and cinnamic acid cores, a structural-specific QSAR model was developed by incorporating geometrical descriptors into the previous general QSAR model, again, with acceptable parameters (

R^{2}

= 85.554,

Q^{2}

_LMO = 80.534,

Q^{2}

_BOOT = 78.186, and

Q^{2}

_EXT = 79.41). Employing this new QSAR model over the natural parent chalcone 2′,4′-DHC (A) and the chimeric compound 2′-hydroxy,4′-cinnamate chalcone (B), the predicted cytotoxic activity was achieved with values of 55.95 and 17.86 µM, respectively. Therefore, to corroborate the predicted cytotoxic activity compounds A and B were synthesized by two- and three-step reactions. The structures were confirmed by ¹H and ¹³C NMR and ESI+MS analysis and further evaluated in vitro against HepG2, Hep3B (liver), A-549 (lung), MCF-7 (breast), and CasKi (cervical) human cancer cell lines. The results showed IC₅₀ values of 11.89, 10.27, 56.75, 14.86, and 29.72 µM, respectively, for the chimeric cinnamate chalcone B. Finally, we employed B as a molecular scaffold for the generation of cinnamate candidates (C–K), which incorporated structural motifs that enhance the cytotoxic activity (pyridine ring, halogens, and methoxy groups) according to our QSAR model. ADME/tox in silico analysis showed that the synthesized compounds A and B, as well as the proposed chalcones C and G, are the best candidates with adequate drug-likeness properties. From all these results, we propose B (as a molecular scaffold) and our two QSAR models as reliable tools for the generation of anti-cancer compounds over the MCF-7 cell line. Full article

(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation)

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35 pages, 5212 KiB

Open AccessArticle

Synthesis, Biological, Spectroscopic and Computational Investigations of Novel N-Acylhydrazone Derivatives of Pyrrolo[3,4-d]pyridazinone as Dual COX/LOX Inhibitors

by Jakub Mikus, Piotr Świątek, Patrycja Przybyła, Edward Krzyżak, Aleksandra Marciniak, Aleksadra Kotynia, Aleksandra Redzicka, Benita Wiatrak, Paulina Jawień, Tomasz Gębarowski and Łukasz Szczukowski

Molecules 2023, 28(14), 5479; https://doi.org/10.3390/molecules28145479 - 18 Jul 2023

Cited by 1 | Viewed by 1171

Abstract

Secure and efficient treatment of diverse pain and inflammatory disorders is continually challenging. Although NSAIDs and other painkillers are well-known and commonly available, they are sometimes insufficient and can cause dangerous adverse effects. As yet reported, derivatives of pyrrolo[3,4-d]pyridazinone are potent [...] Read more.

Secure and efficient treatment of diverse pain and inflammatory disorders is continually challenging. Although NSAIDs and other painkillers are well-known and commonly available, they are sometimes insufficient and can cause dangerous adverse effects. As yet reported, derivatives of pyrrolo[3,4-d]pyridazinone are potent COX-2 inhibitors with a COX-2/COX-1 selectivity index better than meloxicam. Considering that N-acylhydrazone (NAH) moiety is a privileged structure occurring in many promising drug candidates, we decided to introduce this pharmacophore into new series of pyrrolo[3,4-d]pyridazinone derivatives. The current paper presents the synthesis and in vitro, spectroscopic, and in silico studies evaluating the biological and physicochemical properties of NAH derivatives of pyrrolo[3,4-d]pyridazinone. Novel compounds 5a-c–7a-c were received with high purity and good yields and did not show cytotoxicity in the MTT assay. Their COX-1, COX-2, and 15-LOX inhibitory activities were estimated using enzymatic tests and molecular docking studies. The title N-acylhydrazones appeared to be promising dual COX/LOX inhibitors. Moreover, spectroscopic and computational methods revealed that new compounds form stable complexes with the most abundant plasma proteins–AAG and HSA, but do not destabilize their secondary structure. Additionally, predicted pharmacokinetic and drug-likeness properties of investigated molecules suggest their potentially good membrane permeability and satisfactory bioavailability. Full article

(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation)

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15 pages, 4829 KiB

Open AccessArticle

The Benzothiazine Core as a Novel Motif for DNA-Binding Small Molecules

by Milena Mlakić, Ivona Čipor, Petra Kovačec, Goran Kragol, Ana Ratković, Tatjana Kovačević, Rahela Zadravec, Valentina Milašinović, Krešimir Molčanov, Ivo Piantanida and Irena Škorić

Molecules 2023, 28(11), 4499; https://doi.org/10.3390/molecules28114499 - 01 Jun 2023

Cited by 1 | Viewed by 1159

Abstract

A new series of 4H-1,3-benzothiazine dyes were prepared and fully characterized in an aqueous medium. Benzothiazine salts were synthesized either through the classical synthetic pathway using Buchwald–Hartwig amination or through economical and environmentally friendly electrochemical synthesis. The latest synthetic approach employs [...] Read more.

A new series of 4H-1,3-benzothiazine dyes were prepared and fully characterized in an aqueous medium. Benzothiazine salts were synthesized either through the classical synthetic pathway using Buchwald–Hartwig amination or through economical and environmentally friendly electrochemical synthesis. The latest synthetic approach employs successful electrochemical intramolecular dehydrogenative cyclization of N-benzylbenzenecarbothioamides to form 4H-1,3-benzothiazines. 4H-1,3-Benzothiazines were evaluated as novel DNA/RNA probes. Through the use of several methods such as UV/vis spectrophotometric titrations, circular dichroism and thermal melting experiments, the binding of four benzothiazine-based molecules to polynucleotides was examined. Compounds 1 and 2 acted as DNA/RNA groove binders, thus suggesting the potential of these compounds as novel DNA/RNA probes. This is a proof-of-concept study and will be expanded to include SAR/QSAR studies. Full article

(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation)

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18 pages, 974 KiB

Open AccessArticle

Novel Biologically Active N-Substituted Benzimidazole Derived Schiff Bases: Design, Synthesis, and Biological Evaluation

by Anja Beč, Maja Cindrić, Leentje Persoons, Mihailo Banjanac, Vedrana Radovanović, Dirk Daelemans and Marijana Hranjec

Molecules 2023, 28(9), 3720; https://doi.org/10.3390/molecules28093720 - 25 Apr 2023

Cited by 6 | Viewed by 1390

Abstract

Herein, we present the design and synthesis of novel N-substituted benzimidazole-derived Schiff bases, and the evaluation of their antiviral, antibacterial, and antiproliferative activity. The impact on the biological activity of substituents placed at the N atom of the benzimidazole nuclei and the [...] Read more.

Herein, we present the design and synthesis of novel N-substituted benzimidazole-derived Schiff bases, and the evaluation of their antiviral, antibacterial, and antiproliferative activity. The impact on the biological activity of substituents placed at the N atom of the benzimidazole nuclei and the type of substituents attached at the phenyl ring were examined. All of the synthesized Schiff bases were evaluated in vitro for their antiviral activity against different viruses, antibacterial activity against a panel of bacterial strains, and antiproliferative activity on several human cancer cell lines, thus enabling the study of the structure−activity relationships. Some mild antiviral effects were noted, although at higher concentrations in comparison with the included reference drugs. Additionally, some derivatives showed a moderate antibacterial activity, with precursor 23 being broadly active against most of the tested bacterial strains. Lastly, Schiff base 40, a 4-N,N-diethylamino-2-hydroxy-substituted derivative bearing a phenyl ring at the N atom on the benzimidazole nuclei, displayed a strong antiproliferative activity against several cancer cell lines (IC₅₀ 1.1–4.4 μM). The strongest antitumoral effect was observed towards acute myeloid leukemia (HL-60). Full article

(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation)

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13 pages, 1671 KiB

Open AccessArticle

Naphth[1,2-d]imidazoles Bioactive from β-Lapachone: Fluorescent Probes and Cytotoxic Agents to Cancer Cells

by Victória Laysna dos Anjos Santos, Arlan de Assis Gonsalves, Délis Galvão Guimarães, Sidney Silva Simplicio, Helinando Pequeno de Oliveira, Lara Polyana Silva Ramos, Marcília Pinheiro da Costa, Fátima de Cássia Evangelista de Oliveira, Claudia Pessoa and Cleônia Roberta Melo Araújo

Molecules 2023, 28(7), 3008; https://doi.org/10.3390/molecules28073008 - 28 Mar 2023

Cited by 2 | Viewed by 1368

Abstract

Theranostics combines therapeutic and imaging diagnostic techniques that are extremely dependent on the action of imaging agent, transporter of therapeutic molecules, and specific target ligand, in which fluorescent probes can act as diagnostic agents. In particular, naphthoimidazoles are potential bioactive heterocycle compounds to [...] Read more.

Theranostics combines therapeutic and imaging diagnostic techniques that are extremely dependent on the action of imaging agent, transporter of therapeutic molecules, and specific target ligand, in which fluorescent probes can act as diagnostic agents. In particular, naphthoimidazoles are potential bioactive heterocycle compounds to be used in several biomedical applications. With this aim, a group of seven naphth[1,2-d]imidazole compounds were synthesized from β-lapachone. Their optical properties and their cytotoxic activity against cancer cells and their compounds were evaluated and confirmed promising values for molar absorptivity coefficients (on the order of 10³ to 10⁴), intense fluorescence emissions in the blue region, and large Stokes shifts (20–103 nm). Furthermore, the probes were also selective for analyzed cancer cells (leukemic cells (HL-60). The naphth[1,2-d]imidazoles showed IC₅₀ between 8.71 and 29.92 μM against HL-60 cells. For HCT-116 cells, values for IC₅₀ between 21.12 and 62.11 μM were observed. The selective cytotoxicity towards cancer cells and the fluorescence of the synthesized naphth[1,2-d]imidazoles are promising responses that make possible the application of these components in antitumor theranostic systems. Full article

(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation)

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26 pages, 4850 KiB

Open AccessArticle

Synthesis and Biological Evaluation of Novel Dispiro-Indolinones with Anticancer Activity

by Yan A. Ivanenkov, Maxim E. Kukushkin, Anastasia A. Beloglazkina, Radik R. Shafikov, Alexander A. Barashkin, Andrey A. Ayginin, Marina S. Serebryakova, Alexander G. Majouga, Dmitry A. Skvortsov, Viktor A. Tafeenko and Elena K. Beloglazkina

Molecules 2023, 28(3), 1325; https://doi.org/10.3390/molecules28031325 - 30 Jan 2023

Cited by 3 | Viewed by 2051

Abstract

Novel variously substituted thiohydantoin-based dispiro-indolinones were prepared using a regio- and diastereoselective synthetic route from 5-arylidene-2-thiohydantoins, isatines, and sarcosine. The obtained molecules were subsequently evaluated in vitro against the cancer cell lines LNCaP, PC3, HCT^wt, and HCT^(−/−). Several [...] Read more.

Novel variously substituted thiohydantoin-based dispiro-indolinones were prepared using a regio- and diastereoselective synthetic route from 5-arylidene-2-thiohydantoins, isatines, and sarcosine. The obtained molecules were subsequently evaluated in vitro against the cancer cell lines LNCaP, PC3, HCT^wt, and HCT^(−/−). Several compounds demonstrated a relatively high cytotoxic activity vs. LNCaP cells (IC₅₀ = 1.2–3.5 µM) and a reasonable selectivity index (SI = 3–10). Confocal microscopy revealed that the conjugate of propargyl-substituted dispiro-indolinone with the fluorescent dye Sulfo-Cy5-azide was mainly localized in the cytoplasm of HEK293 cells. P388-inoculated mice and HCT116-xenograft BALB/c nude mice were used to evaluate the anticancer activity of compound 29 in vivo. Particularly, the TGRI value for the P388 model was 93% at the final control timepoint. No mortality was registered among the population up to day 31 of the study. In the HCT116 xenograft model, the compound (170 mg/kg, i.p., o.d., 10 days) provided a T/C ratio close to 60% on day 8 after the treatment was completed. The therapeutic index—estimated as LD₅₀/ED₅₀—for compound 29 in mice was ≥2.5. Molecular docking studies were carried out to predict the possible binding modes of the examined molecules towards MDM2 as the feasible biological target. However, such a mechanism was not confirmed by Western blot data and, apparently, the synthesized compounds have a different mechanism of cytotoxic action. Full article

(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation)

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27 pages, 4979 KiB

Open AccessArticle

Novel 7-Chloro-4-aminoquinoline-benzimidazole Hybrids as Inhibitors of Cancer Cells Growth: Synthesis, Antiproliferative Activity, in Silico ADME Predictions, and Docking

by Luka Krstulović, Marijana Leventić, Vesna Rastija, Kristina Starčević, Maja Jirouš, Ivana Janić, Maja Karnaš, Kornelija Lasić, Miroslav Bajić and Ljubica Glavaš-Obrovac

Molecules 2023, 28(2), 540; https://doi.org/10.3390/molecules28020540 - 05 Jan 2023

Cited by 9 | Viewed by 1993

Abstract

In this study, new 7-chloro-4-aminoquinoline-benzimidazole compounds were synthesized and characterized by NMR, MS, and elemental analysis. These novel hybrids differ in the type of linker and in the substituent on the benzimidazole moiety. Their antiproliferative activities were evaluated on one non-tumor (MDCK1) and [...] Read more.

In this study, new 7-chloro-4-aminoquinoline-benzimidazole compounds were synthesized and characterized by NMR, MS, and elemental analysis. These novel hybrids differ in the type of linker and in the substituent on the benzimidazole moiety. Their antiproliferative activities were evaluated on one non-tumor (MDCK1) and seven selected tumor (CaCo-2, MCF-7, CCRF-CEM, Hut78, THP-1, and Raji) cell lines by MTT test and flow cytometry analysis. The compounds with different types of linkers and an unsubstituted benzimidazole ring, 5d, 8d, and 12d, showed strong cytotoxic activity (the GI₅₀ ranged from 0.4 to 8 µM) and effectively suppressed the cell cycle progression in the leukemia and lymphoma cells. After 24 h of treatment, compounds 5d and 12d induced the disruption of the mitochondrial membrane potential as well as apoptosis in HuT78 cells. The drug-like properties and bioavailability of the compounds were calculated using the Swiss ADME web tool, and a molecular docking study was performed on tyrosine-protein kinase c-Src (PDB: 3G6H). Compound 12d showed good solubility and permeability and bound to c-Src with an energy of −119.99 kcal/mol, forming hydrogen bonds with Glu310 and Asp404 in the active site and other residues with van der Waals interactions. The results suggest that compound 12d could be a leading compound in the further design of effective antitumor drugs. Full article

(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation)

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29 pages, 4405 KiB

Open AccessArticle

Inhibition of Cancer Cell Proliferation and Bacterial Growth by Silver(I) Complexes Bearing a CH₃-Substituted Thiadiazole-Based Thioamide

by Despoina Varna, Elena Geromichalou, Georgia Karlioti, Rigini Papi, Panagiotis Dalezis, Antonios G. Hatzidimitriou, George Psomas, Theodora Choli-Papadopoulou, Dimitrios T. Trafalis and Panagiotis A. Angaridis

Molecules 2023, 28(1), 336; https://doi.org/10.3390/molecules28010336 - 01 Jan 2023

Cited by 2 | Viewed by 1986

Abstract

Ag(I) coordination compounds have recently attracted much attention as antiproliferative and antibacterial agents against a wide range of cancer cell lines and pathogens. The bioactivity potential of these complexes depends on their structural characteristics and the nature of their ligands. Herein, we present [...] Read more.

Ag(I) coordination compounds have recently attracted much attention as antiproliferative and antibacterial agents against a wide range of cancer cell lines and pathogens. The bioactivity potential of these complexes depends on their structural characteristics and the nature of their ligands. Herein, we present a series of four Ag(I) coordination compounds bearing as ligands the CH₃-substituted thiadiazole-based thioamide 5-methyl-1,3,4-thiadiazole-2-thiol (mtdztH) and phosphines, i.e., [AgCl(mtdztH)(PPh₃)₂] (1), [Ag(mtdzt)(PPh₃)₃] (2), [AgCl(mtdztH)(xantphos)] (3), and [AgmtdztH)(dppe)(NO₃)]_n (4), where xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and dppe = 1,2-bis(diphenylphosphino)ethane, and the assessment of their in vitro antibacterial and anti-cancer efficiency. Among them, diphosphine-containing compounds 3 and 4 were found to exhibit broad-spectrum antibacterial activity characteristics against both Gram-(+) and Gram-(–) bacterial strains, showing high in vitro bioactivity with IC₅₀ values as low as 4.6 μΜ. In vitro cytotoxicity studies against human ovarian, pancreatic, lung, and prostate cancer cell lines revealed the strong cytotoxic potential of 2 and 4, with IC₅₀ values in the range of 3.1–24.0 μΜ, while 3 and 4 maintained the normal fibroblast cells’ viability at relatively higher levels. Assessment of these results, in combination with those obtained for analogous Ag(I) complexes bearing similar heterocyclic thioamides, suggest the pivotal role of the substituent groups of the thioamide heterocyclic ring in the antibacterial and anti-cancer efficacy of the respective Ag(I) complexes. Compounds 1–4 exhibited moderate in vitro antioxidant capacity for free radicals scavenging, as well as reasonably strong ability to interact with calf-thymus DNA, suggesting the likely implication of these properties in their bioactivity mechanisms. Complementary insights into the possible mechanism of their anti-cancer activity were provided by molecular docking calculations, exploring their ability to bind to the overexpressed fibroblast growth factor receptor 1 (FGFR1), affecting cancer cells’ functionalities. Full article

(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation)

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19 pages, 3116 KiB

Open AccessArticle

Synthesis and Anticancer Activity of 1,3,4-Thiadiazoles with 3-Methoxyphenyl Substituent

by Sara Janowska, Dmytro Khylyuk, Agnieszka Gornowicz, Anna Bielawska, Michał Janowski, Robert Czarnomysy, Krzysztof Bielawski and Monika Wujec

Molecules 2022, 27(20), 6977; https://doi.org/10.3390/molecules27206977 - 17 Oct 2022

Cited by 4 | Viewed by 1584

Abstract

Based on the results of previous work, we designed and synthesized 1,3,4-thiadiazole derivatives. The cytotoxic activity of the obtained compounds was then determined in biological studies using MCF-7 and MDA-MB-231 breast cancer cells and a normal cell line (fibroblasts). The results showed that [...] Read more.

Based on the results of previous work, we designed and synthesized 1,3,4-thiadiazole derivatives. The cytotoxic activity of the obtained compounds was then determined in biological studies using MCF-7 and MDA-MB-231 breast cancer cells and a normal cell line (fibroblasts). The results showed that all compounds displayed weak anticancer activity towards two breast cancer lines: an estrogen-dependent cell line (MCF-7) and an estrogen-independent cell line (MDA-MB-231). The compound most active towards MCF-7 breast cancer cells was SCT-4, which decreased DNA biosynthesis to 70% ± 3 at 100 µM. The mechanism of the anticancer action of 1,3,4-thiadiazole was also investigated. We choose a set of the most investigated proteins, which are attractive anticancer targets. In silico studies demonstrated a possible multitarget mode of action for the synthesized compounds but the most likely mechanism of action for the new compounds is connected with the activity of caspase 8. Full article

(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation)

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Review

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16 pages, 2515 KiB

Open AccessReview

Can We Improve Diosmetin Activity? The State-of-the-Art and Promising Research Directions

by Monika Wujec and Marcin Feldo

Molecules 2023, 28(23), 7910; https://doi.org/10.3390/molecules28237910 - 02 Dec 2023

Viewed by 939

Abstract

Diosmetin is a natural substance widely distributed in nature, with documented multidirectional biological effects. The wide spectrum of biological activity of diosmetin gives hope that derivatives of this flavonoid may also be used as drugs or dietary supplements used in many diseases. Modification [...] Read more.

Diosmetin is a natural substance widely distributed in nature, with documented multidirectional biological effects. The wide spectrum of biological activity of diosmetin gives hope that derivatives of this flavonoid may also be used as drugs or dietary supplements used in many diseases. Modification of the structure may, on the one hand, lead to an increase in biological potency, new biological activity, or an increase in solubility and thus bioavailability. This is an important direction of research because the use of pure diosmetin is limited due to its low bioavailability. This work is an attempt to collect information on the possibility of modifying the structure of diosmetin and its impact on biological activity. Full article

(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation)

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25 pages, 11885 KiB

Open AccessReview

NRF2 Activation by Nitrogen Heterocycles: A Review

by Melford C. Egbujor, Paolo Tucci, Ugomma C. Onyeije, Chigbundu N. Emeruwa and Luciano Saso

Molecules 2023, 28(6), 2751; https://doi.org/10.3390/molecules28062751 - 18 Mar 2023

Cited by 5 | Viewed by 2155

Abstract

Several nitrogen heterocyclic analogues have been applied to clinical practice, and about 75% of drugs approved by the FDA contain at least a heterocyclic moiety. Thus, nitrogen heterocycles are beneficial scaffolds that occupy a central position in the development of new drugs. The [...] Read more.

Several nitrogen heterocyclic analogues have been applied to clinical practice, and about 75% of drugs approved by the FDA contain at least a heterocyclic moiety. Thus, nitrogen heterocycles are beneficial scaffolds that occupy a central position in the development of new drugs. The fact that certain nitrogen heterocyclic compounds significantly activate the NRF2/ARE signaling pathway and upregulate the expression of NRF2-dependent genes, especially HO-1 and NQO1, underscores the need to study the roles and pharmacological effects of N-based heterocyclic moieties in NRF2 activation. Furthermore, nitrogen heterocycles exhibit significant antioxidant and anti-inflammatory activities. NRF2-activating molecules have been of tremendous research interest in recent times due to their therapeutic roles in neuroinflammation and oxidative stress-mediated diseases. A comprehensive review of the NRF2-inducing activities of N-based heterocycles and their derivatives will broaden their therapeutic prospects in a wide range of diseases. Thus, the present review, as the first of its kind, provides an overview of the roles and effects of nitrogen heterocyclic moieties in the activation of the NRF2 signaling pathway underpinning their antioxidant and anti-inflammatory actions in several diseases, their pharmacological properties and structural–activity relationship are also discussed with the aim of making new discoveries that will stimulate innovative research in this area. Full article

(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation)

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