Selected Papers from the 7th International Electronic Conference on Medicinal Chemistry (ECMC2021)

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

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 20520

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Formerly Head, Department of Organic Chemistry (FS), University of Mons-UMONS, 7000 Mons, Belgium
Interests: heterocycles; medicinal chemistry; green chemistry; microwave-induced synthesis
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Dear Colleagues,

The seventh edition of our series of electronic conferences on medicinal chemistry (https://ecmc2021.sciforum.net/) was hosted on the online platform “sciforum.net” from November 1 to November 30, 2021. Thanks to participants and visitors from the five continents, the virtual event was a great success, and the exceptional quality of the submissions made rewarding the most outstanding works extremely difficult. In this Special Issue, we wish to present a range of the featured topics disclosed during the conference.

Dr. Jean Jacques Vanden Eynde
Dr.Annie Mayence
Guest Editors

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Published Papers (9 papers)

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Research

13 pages, 1901 KiB  
Article
Fluoroquinolone Derivatives in the Treatment of Mycobacterium tuberculosis Infection
by João Pedro Pais, Margarida Policarpo, David Pires, Ana Paula Francisco, Ana Margarida Madureira, Bernard Testa, Elsa Anes and Luís Constantino
Pharmaceuticals 2022, 15(10), 1213; https://doi.org/10.3390/ph15101213 - 30 Sep 2022
Cited by 1 | Viewed by 1861
Abstract
Tuberculosis (TB) is currently one of the leading causes of death due to infective agents, and the growing rate of multidrug-resistant tuberculosis (MDR TB) cases poses an emergent public health threat. Fluoroquinolones are commonly used in the treatment of both MDR TB and [...] Read more.
Tuberculosis (TB) is currently one of the leading causes of death due to infective agents, and the growing rate of multidrug-resistant tuberculosis (MDR TB) cases poses an emergent public health threat. Fluoroquinolones are commonly used in the treatment of both MDR TB and drug-sensitive tuberculosis patients who are intolerant to first-line antitubercular agents. Unfortunately, these drugs have mild side effects, relevant to the prolonged treatment regimens and diminished bioavailability due to binding of metal ions. Moreover, the resistance to fluoroquinolones is also on the rise, a characteristic of extensively drug-resistant TB (XDR TB). Here, we developed esters as prodrugs of the fluoroquinolones levofloxacin and ciprofloxacin, with long-chain fatty alcohols. Both the alcohols and the quinolone have previously shown antimycobacterial activity and the aim was to develop esters with improved lipophilicity and capable of delivering the free acid inside mycobacterial cells. The carboxylic acid group of fluoroquinolones is essential to the mode of action but is also responsible for many of its side effects and metal-chelating properties. The synthesis, stability in biological media, and antibacterial activity were evaluated, the latter not only against Mycobacterium tuberculosis but also against other clinically relevant bacterial species, since the parent compounds display a broad spectrum of activity. The biological results show a reduction in the antitubercular activity of the synthesized derivatives, probably due to deficient activation of the ester prodrug. Despite this, it was found that the derivatives exhibit bioactivity against other fluoroquinolone-resistant bacteria, indicating a different mode of action and suggesting that it may be worthwhile to research further modifications to the carboxylic acid group. This might lead to new compounds that are efficient against resistant strains. This idea that the compounds may act by a different mechanism of action was further supported by a brief computer investigation that demonstrated the potential lack of selectivity of the esters to the fluoroquinolone target. Full article
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11 pages, 2419 KiB  
Article
The Synthetic Cannabinoid URB447 Exerts Antitumor and Antimetastatic Effect in Melanoma and Colon Cancer
by Aitor Benedicto, Beatriz Arteta, Andrea Duranti and Daniel Alonso-Alconada
Pharmaceuticals 2022, 15(10), 1166; https://doi.org/10.3390/ph15101166 - 20 Sep 2022
Cited by 6 | Viewed by 2070
Abstract
The endocannabinoid system is widespread through the body and carries out a wide variety of functions. However, its involvement in other pathologies, such as cancer, still needs further attention. We aim to investigate the role of CB2 receptor during melanoma and colorectal cancer [...] Read more.
The endocannabinoid system is widespread through the body and carries out a wide variety of functions. However, its involvement in other pathologies, such as cancer, still needs further attention. We aim to investigate the role of CB2 receptor during melanoma and colorectal cancer (CRC) aggressiveness and metastatic growth in the liver. We used the synthetic cannabinoid URB447, a known CB2 agonist and CB1 antagonist drug, and studied prometastatic ability of mouse B16 melanoma and MCA38 CRC cells, by means of proliferation, apoptosis, cell cycle, migration and matrix degradation in vitro upon URB447 treatment. We reported a dose-dependent viability decrease in both tumor types. This result is partly mediated by apoptotic cell death and cell cycle arrest in G1/G0 phase, as observed through flow cytometry. Melanoma and CRC cell migration was affected in a dose-dependent fashion as observed through scratch assay, whereas the secretion of matrix degrading proteins metalloprotease 2 (MMP2) and 9 (MMP9) in tumor cells did not significantly change. Moreover, daily treatment of tumor bearing mice with URB447 decreased the development of liver metastasis in a melanoma model in vivo. This proof of concept study points out to the synthetic cannabinoid URB447 as a potential candidate for deeper studies to confirm its potential as antitumor therapy and liver metastasis treatment for CRC and melanoma. Full article
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10 pages, 1298 KiB  
Article
Benzoic Acid Derivatives as Prodrugs for the Treatment of Tuberculosis
by João P. Pais, Marta Magalhães, Olha Antoniuk, Ivete Barbosa, Raquel Freire, David Pires, Emília Valente, Bernard Testa, Elsa Anes and Luis Constantino
Pharmaceuticals 2022, 15(9), 1118; https://doi.org/10.3390/ph15091118 - 07 Sep 2022
Cited by 2 | Viewed by 2169
Abstract
One interesting approach to fight tuberculosis is the use of prodrugs that often have shown improved biological activities over drugs with poor absorption or difficulty to cross membranes. Previous studies demonstrate that weak acids such as benzoic acid, present antimycobacterial activity. Moreover, esters [...] Read more.
One interesting approach to fight tuberculosis is the use of prodrugs that often have shown improved biological activities over drugs with poor absorption or difficulty to cross membranes. Previous studies demonstrate that weak acids such as benzoic acid, present antimycobacterial activity. Moreover, esters of those acids revealed to be a viable alternative since they may diffuse more easily through the cell membranes. Previously we showed that mycobacteria can easily activate benzoic acid esters by conversion to the corresponding acid. Since Zhang postulated that the activity of the acids can be dependent on their pKa, we set up to synthesize a library of benzoates with different electron withdrawing groups (4-chloro, 2,6-dichloro, 3,5-dichloro, 4-nitro, and 3,5 dinitro), to modulate pKa of the liberated acid and different alkoxy substituents (propyl, hexyl, and phenyl) to modulate their lipophilicity, and tested the activity of the esters and the corresponding free acids against mycobacteria. We also studied the activation of the esters by mycobacterial enzymes and the stability of the compounds in buffer and plasma. We concluded that all the benzoates in our study can be activated by mycobacterial enzymes and that the phenyl and hexyl esters presented higher activity than the corresponding free acids, with the nitrobenzoates, and especially the dinitrobenzoates, showing very interesting antitubercular activity that deserve further exploration. Our results did not show a correlation between the activity and the pKa of the acids. Full article
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11 pages, 444 KiB  
Article
Antiplasmodial Activity of Vachellia xanthophloea (Benth.) P.J.H. Hurter (African Fever Tree) and Its Constituents
by Nasir Tajuddeen, Tarryn Swart, Heinrich C. Hoppe and Fanie R. van Heerden
Pharmaceuticals 2022, 15(4), 470; https://doi.org/10.3390/ph15040470 - 13 Apr 2022
Cited by 4 | Viewed by 2721
Abstract
Vachellia xanthophloea is used in Zulu traditional medicine as an antimalarial remedy. A moderate antiplasmodial activity was previously reported for extracts of the plant against D10 Plasmodium falciparum. This study aimed to identify the phytochemicals responsible for the antiplasmodial activity of the [...] Read more.
Vachellia xanthophloea is used in Zulu traditional medicine as an antimalarial remedy. A moderate antiplasmodial activity was previously reported for extracts of the plant against D10 Plasmodium falciparum. This study aimed to identify the phytochemicals responsible for the antiplasmodial activity of the leaf extract. The compounds were isolated by chromatography and their structures were determined using spectroscopic and spectrometric methods. The antiplasmodial activity was evaluated using a parasite lactate dehydrogenase assay and cytotoxicity was determined using a resazurin assay. The ethyl acetate fraction inhibited P. falciparum with IC50 = 10.6 µg/mL and showed minimal cytotoxicity (98% cell viability at 33 µg/mL). The chromatographic purification of this fraction afforded sixteen compounds, including two new flavonoids. A 1:1 mixture of phytol and lupeol was also isolated from the hexane fraction. All the compounds were reported from V. xanthophloea for the first time. Among the isolated metabolites, methyl gallate displayed the best activity against P. falciparum (IC50 = 1.2 µg/mL), with a 68% viability of HeLa cells at 10 µg/mL. Therefore, methyl gallate was responsible for the antiplasmodial activity of the V. xanthophloea leaf extract and its presence in the leaf extract might account for the folkloric use of the plant as an antimalarial remedy. Full article
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8 pages, 1146 KiB  
Communication
Protein-Based Delivery Systems for Anticancer Metallodrugs: Structure and Biological Activity of the Oxaliplatin/β-Lactoglobulin Adduct
by Daria Maria Monti, Domenico Loreto, Ilaria Iacobucci, Giarita Ferraro, Alessandro Pratesi, Luigi D’Elia, Maria Monti and Antonello Merlino
Pharmaceuticals 2022, 15(4), 425; https://doi.org/10.3390/ph15040425 - 30 Mar 2022
Cited by 6 | Viewed by 2135
Abstract
β-lactoglobulin is the major component of whey. Here, the adduct formed upon the reaction of the protein with oxaliplatin (OXA) has been prepared, structurally characterized by X-ray crystallography and electrospray ionization–mass spectrometry, and evaluated as a cytotoxic agent. The data demonstrate that OXA [...] Read more.
β-lactoglobulin is the major component of whey. Here, the adduct formed upon the reaction of the protein with oxaliplatin (OXA) has been prepared, structurally characterized by X-ray crystallography and electrospray ionization–mass spectrometry, and evaluated as a cytotoxic agent. The data demonstrate that OXA rapidly binds β-lactoglobulin via coordination with a Met7 side chain upon release of the oxalate ligand. The adduct is significantly more cytotoxic than the free drug and induces apoptosis in cancer cells. Overall, our results suggest that metallodrug/β-lactoglobulin adducts can be used as anticancer agents and that the protein can be used as a metallodrug delivery system. Full article
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9 pages, 5262 KiB  
Article
Structural Insight of New Butyrylcholinesterase Inhibitors Based on Benzylbenzofuran Scaffold
by Giovanna L. Delogu, Antonella Fais, Francesca Pintus, Chinmayi Goyal, Maria J. Matos, Benedetta Era and Amit Kumar
Pharmaceuticals 2022, 15(3), 304; https://doi.org/10.3390/ph15030304 - 02 Mar 2022
Cited by 3 | Viewed by 1927
Abstract
In the present work, we use a merger of computational and biochemical techniques as a rational guideline for structural modification of benzofuran derivatives to find pertinent structural features for the butyrylcholinesterase inhibitory activity and selectivity. Previously, we revealed a series of 2-phenylbenzofuran compounds [...] Read more.
In the present work, we use a merger of computational and biochemical techniques as a rational guideline for structural modification of benzofuran derivatives to find pertinent structural features for the butyrylcholinesterase inhibitory activity and selectivity. Previously, we revealed a series of 2-phenylbenzofuran compounds that displayed a selective inhibitory activity for BChE. Here, in an effort to discover novel selective BChE inhibitors with favorable physicochemical and pharmacokinetic profiles, 2-benzylbenzofurans were designed, synthesized, and evaluated as BChE inhibitors. The 2-phenylbenzofuran scaffold structure is modified by introducing one methylene spacer between the benzofuran core and the 2-phenyl ring with a hydroxyl substituent in the para or meta position. Either position 5 or 7 of the benzofuran scaffold was substituted with a bromine or chlorine atom. Further assessment of the selected list of compounds indicated that the substituent’s nature and position determined their activity and selectivity. 5-bromo-2-(4-hydroxybenzyl)benzofuran 9B proved to be the most potent butyrylcholinesterase inhibitor (IC50 = 2.93 µM) of the studied series. Computational studies were carried out to correlate the theoretical and experimental binding affinity of the compounds to the BChE protein. Full article
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16 pages, 3827 KiB  
Article
2-Styrylchromones: Cytotoxicity and Modulation of Human Neutrophils’ Oxidative Burst
by Mariana Lucas, Marisa Freitas, Marco Zanchetta, Artur M. S. Silva, Eduarda Fernandes and Daniela Ribeiro
Pharmaceuticals 2022, 15(3), 288; https://doi.org/10.3390/ph15030288 - 25 Feb 2022
Cited by 2 | Viewed by 2686
Abstract
Neutrophils are polymorphonuclear leukocytes recruited to sites of acute inflammation, in response to pathogen invasion and tissue injury. The modulation of their activity, especially oxidative burst, may be important to control the inflammatory process. 2-Styrylchromones (2-SC) are derived from chromones and despite their [...] Read more.
Neutrophils are polymorphonuclear leukocytes recruited to sites of acute inflammation, in response to pathogen invasion and tissue injury. The modulation of their activity, especially oxidative burst, may be important to control the inflammatory process. 2-Styrylchromones (2-SC) are derived from chromones and despite their recognized multiple biological activities, their anti-inflammatory and antioxidant properties are still poorly explored. Therefore, in this study, 43 structurally related 2-SC were evaluated concerning their effects on freshly isolated human neutrophils’ viability and oxidative burst. The studied 2-SC were divided into eight groups according to their substitution at C-4′ on B-ring (none, -OH, -OCH3, -OBn, -CH3, and -NO2), existence and location of -Cl on B-ring, and presence of -Br at C-3 on C-ring. Overall, most of the studied 2-SC did not affect neutrophils’ viability, at physiological relevant concentrations. The ones belonging to B group were the most effective (IC50 values < 2 μM), and present one -OH group at C-4′ or a catechol group at C-3′ and C-4′ on B-ring. These substituents seem to play an important role in the modulatory activity of human neutrophils’ oxidative burst. These results reinforce the great potential of 2-SC’s scaffold for the development of new anti-inflammatory agents. Full article
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16 pages, 42300 KiB  
Article
Effect of Caffeine and Flavonoids on the Binding of Tigecycline to Human Serum Albumin: A Spectroscopic Study and Molecular Docking
by Miroslav Sovrlić, Emina Mrkalić, Ratomir Jelić, Marina Ćendić Serafinović, Stefan Stojanović, Nevena Prodanović and Jovica Tomović
Pharmaceuticals 2022, 15(3), 266; https://doi.org/10.3390/ph15030266 - 22 Feb 2022
Cited by 5 | Viewed by 1997
Abstract
Human serum albumin (HSA) has a very significant role in the transport of drugs, in their pharmacokinetic and pharmacodynamic properties, as well as the unbound concentration of drugs in circulating plasma. The aim of this study was to look into the competition between [...] Read more.
Human serum albumin (HSA) has a very significant role in the transport of drugs, in their pharmacokinetic and pharmacodynamic properties, as well as the unbound concentration of drugs in circulating plasma. The aim of this study was to look into the competition between tigecycline (TGC) and alkaloid (ALK) (caffeine (CAF)), and flavonoids (FLAVs) (catechin (CAT), quercetin (QUE), and diosmin (DIO)) in binding to HSA in simulated physiological conditions using multiple spectroscopic measurements and docking simulations. Fluorescence analysis was used to find the binding and quenching properties of double HSA-TGC and triple HSA-TGC-CAF/FLAV systems. The conformational change of the HSA was analyzed using synchronous fluorescence spectroscopy, Fourier transform infrared spectroscopy, and circular dichroism. Obtained results of spectroscopic analyses indicate that triple complexes of HSA-TGC-CAF/FLAVs are formed without problems and have higher binding affinities than double HSA-TGC. In addition, TGC does not change the microenvironments around the tryptophan (Trp) and tyrosine (Tyr) residues in the presence of ALK and FLAVs. Ultimately, the binding affinity, competition, and interaction nature were explored by docking modeling. Computational outcomes are in good accordance with experimentally obtained results. Accordingly, concluding remarks may be very useful for potential interactions between common food components and drugs. Full article
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18 pages, 9730 KiB  
Article
Microwave-Assisted Synchronous Nanogold Synthesis Reinforced by Kenaf Seed and Decoding Their Biocompatibility and Anticancer Activity
by Md. Adnan, Ki-Kwang Oh, Azamal Husen, Myeong-Hyeon Wang, Madhusudhan Alle and Dong-Ha Cho
Pharmaceuticals 2022, 15(2), 111; https://doi.org/10.3390/ph15020111 - 18 Jan 2022
Cited by 5 | Viewed by 1738
Abstract
The combination of green-nanotechnology and biology may contribute to anticancer therapy. In this regard, using gold nanoparticles (GNPs) as therapeutic molecules can be a promising strategy. Herein, we proposed a novel biocompatible nanogold constructed by simply microwave-heating (MWI) Au3+ ions and kenaf [...] Read more.
The combination of green-nanotechnology and biology may contribute to anticancer therapy. In this regard, using gold nanoparticles (GNPs) as therapeutic molecules can be a promising strategy. Herein, we proposed a novel biocompatible nanogold constructed by simply microwave-heating (MWI) Au3+ ions and kenaf seed (KS) extract within a minute. The phytoconstituents of KS extract have been utilized for safe synthesis of gold nanoparticles (KS@GNPs). The biogenic KS@GNPs were characterized by UV-vis Spectra, TEM, HR-TEM, XRD, FTIR, DLS, EDX, and SEAD techniques. The legitimacy and toxicity concern of KS@GNPs were tested against RAW 264.7 and NIH3T3 cell lines. The anticancer efficacy was verified using LN-229 cells. The pathways of KS@GNPs synthesis were optimized by varying the KS concentration (λmax 528 nm), gold salt amount (λmax 524 nm), and MWI times (λmax 522 nm). TEM displayed spherical shape and narrow size distribution (5–19.5 nm) of KS@GNPs, whereas DLS recorded Z-average size of 121.7 d·nm with a zeta potential of −33.7 mV. XRD and SAED ring patterns confirmed the high crystallinity and crystalline face centered cubic structure of gold. FTIR explored OH functional group involved in Au3+ ions reduction followed by GNPs stabilization. KS@GNPs exposure to RAW 264.7 and NIH3T3 cell lines did not induce toxicity while dose-dependent overt cell toxicity and reduced cell viability (26.6%) was observed in LN-229 cells. Moreover, the IC50 (18.79 µg/mL) treatment to cancer cell triggered cellular damages, excessive ROS generation, and apoptosis. Overall, this research exploits a sustainable method of KS@GNPs synthesis and their anticancer therapy. Full article
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