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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 June 2024) | Viewed by 20065

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Prof. Dr. Josef Jampilek

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1. Department of Analytical Chemistry, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, 84215 Bratislava, Slovakia
2. Department of Chemical Biology, Faculty of Science, Palacky University, Olomouc, Slechtitelu 27, 78371 Olomouc, Czech Republic
Interests: medicinal chemistry; drug design; structure–activity relationships; pharmaceutical analysis; polymorphism; drug bioavailability; ADME; nanoparticles; nanoformulations; controlled/targeted delivery
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Dear Colleagues,

We announce with great pleasure the second edition of “Heterocycles in Medicinal Chemistry II”.

Heteroatoms constitute a very common fragment of a number of active pharmaceutical ingredients, as well as excipients; from the point of view of significance, it is all the same if these are isosterically/bioisosterically replaced carbons/carbon substructures in aliphatic structures or real heterocycles. Many heterocyclic scaffolds can be considered as privilege structures. Most frequently, nitrogen heterocycles or various positional combinations of nitrogen atoms, sulphur and oxygen in five- or six-membered rings can be found. According to statistics, more than 85% of all biologically-active chemical entities contain a heterocycle. This fact reflects the central role of heterocycles in modern drug design. The application of heterocycles provides a useful tool for modification of solubility, lipophilicity, polarity and hydrogen bonding capacity of biologically active agents, which results in the optimization of the ADME/Tox properties of drugs or drug candidates. The increasing presence of various heterocycles in drugs is related to advances in synthetic methodologies, such as metal-catalysed cross-coupling and hetero-coupling reactions, that allow rapid access to a wide variety of functionalized heterocycles. On the other hand, many heterocyclic lead compounds were isolated from natural resources, and their structures were subsequently simplified and modified by medicinal chemists. Thus, heterocycles have critical importance for medicinal chemists, because using them, it is possible to expand the available drug-like chemical space and drive more effective drug discovery programs. As medicinal chemistry is “a chemistry-based discipline, also involving aspects of biological, medical and pharmaceutical sciences” and “concerned with the invention, discovery, design, identification and preparation of biologically active compounds, the study of their metabolism, the interpretation of their mode of action at the molecular level and the construction of structure-activity relationships”, this Special Issue of Molecules titled “Heterocycles in Medicinal Chemistry” is devoted to the following research topics focused on heterocycles: (i) synthesis and analysis; (ii) natural compounds; (iii) carbohydrates; (iv) drug design; (v) in silico investigations; (vi) biological screening; (vii) chemical biology and biological chemistry; (vii) biomaterials; and in general, other topics related to heterocycles.

Prof. Dr. Josef Jampilek
Guest Editor

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Keywords

drugs
heterocycles
pharmacophore
drug design
computer study
synthesis
analysis
natural compounds
carbohydrates
physicochemical properties
ADMET
biological screening
chemical biology
biological chemistry
biomaterials

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Related Special Issues

Heterocycles in Medicinal Chemistry in Molecules (20 articles)
Heterocycles in Medicinal Chemistry III in Molecules (4 articles)

Published Papers (11 papers)

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Editorial

Jump to: Research, Review

4 pages, 563 KiB

Open AccessEditorial

Heterocycles in Medicinal Chemistry II

by Josef Jampilek

Molecules 2024, 29(20), 4810; https://doi.org/10.3390/molecules29204810 - 11 Oct 2024

Viewed by 523

Abstract

Carbon has a unique position among the elements, due to the fact that its valence shell has four electrons and is therefore quadrivalent in the excited state [...] Full article

(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry II)

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Research

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19 pages, 7990 KiB

Open AccessArticle

Investigation of the Efficacy of Benzylidene-3-methyl-2-thioxothiazolidin-4-one Analogs with Antioxidant Activities on the Inhibition of Mushroom and Mammal Tyrosinases

by Hye Jin Kim, Hee Jin Jung, Young Eun Kim, Daeun Jeong, Hyeon Seo Park, Hye Soo Park, Dongwan Kang, Yujin Park, Pusoon Chun, Hae Young Chung and Hyung Ryong Moon

Molecules 2024, 29(12), 2887; https://doi.org/10.3390/molecules29122887 - 18 Jun 2024

Cited by 2 | Viewed by 709

Abstract

Based on the fact that substances with a β-phenyl-α,β-unsaturated carbonyl (PUSC) motif confer strong tyrosinase inhibitory activity, benzylidene-3-methyl-2-thioxothiazolidin-4-one (BMTTZD) analogs 1–8 were prepared as potential tyrosinase inhibitors. Four analogs (1–3 and 5) inhibited mushroom tyrosinase strongly. Especially, analog 3 showed an inhibitory effect that was 220 and 22 times more powerful than kojic acid in the presence of l-tyrosine and l-dopa, respectively. A kinetic study utilizing mushroom tyrosinase showed that analogs 1 and 3 competitively inhibited tyrosinase, whereas analogs 2 and 5 inhibited tyrosinase in a mixed manner. A docking simulation study indicated that analogs 2 and 5 could bind to both the tyrosinase active and allosteric sites with high binding affinities. In cell-based experiments using B16F10 cells, analogs 1, 3, and 5 effectively inhibited melanin production; their anti-melanogenic effects were attributed to their ability to inhibit intracellular tyrosinase activity. Moreover, analogs 1, 3, and 5 inhibited in situ B16F10 cellular tyrosinase activity. In three antioxidant experiments, analogs 2 and 3 exhibited strong antioxidant efficacy, similar to that of the positive controls. These results suggest that the BMTTZD analogs are promising tyrosinase inhibitors for the treatment of hyperpigmentation-related disorders. Full article

(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry II)

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17 pages, 1085 KiB

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Design, Synthesis and Biological Activity of Novel Methoxy- and Hydroxy-Substituted N-Benzimidazole-Derived Carboxamides

by Anja Beč, Katarina Zlatić, Mihailo Banjanac, Vedrana Radovanović, Kristina Starčević, Marijeta Kralj and Marijana Hranjec

Molecules 2024, 29(9), 2138; https://doi.org/10.3390/molecules29092138 - 4 May 2024

Cited by 2 | Viewed by 1045

Abstract

This work presents the design, synthesis and biological activity of novel N-substituted benzimidazole carboxamides bearing either a variable number of methoxy and/or hydroxy groups. The targeted carboxamides were designed to investigate the influence of the number of methoxy and/or hydroxy groups, the type of substituent placed on the N atom of the benzimidazole core and the type of substituent placed on the benzimidazole core on biological activity. The most promising derivatives with pronounced antiproliferative activity proved to be N-methyl-substituted derivatives with hydroxyl and methoxy groups at the phenyl ring and cyano groups on the benzimidazole nuclei with selective activity against the MCF-7 cell line (IC₅₀ = 3.1 μM). In addition, the cyano-substituted derivatives 10 and 11 showed strong antiproliferative activity against the tested cells (IC₅₀ = 1.2–5.3 μM). Several tested compounds showed significantly improved antioxidative activity in all three methods compared to standard BHT. In addition, the antioxidative activity of 9, 10, 32 and 36 in the cells generally confirmed their antioxidant ability demonstrated in vitro. However, their antiproliferative activity was not related to their ability to inhibit oxidative stress nor to their ability to induce it. Compound 8 with two hydroxy and one methoxy group on the phenyl ring showed the strongest antibacterial activity against the Gram-positive strain E. faecalis (MIC = 8 μM). Full article

(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry II)

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22 pages, 2983 KiB

Open AccessArticle

F16 Hybrids Derived from Steviol or Isosteviol Are Accumulated in the Mitochondria of Tumor Cells and Overcome Drug Resistance

by Niels V. Heise, Julia Heisig, Kristof Meier, René Csuk and Thomas Mueller

Molecules 2024, 29(2), 381; https://doi.org/10.3390/molecules29020381 - 12 Jan 2024

Cited by 3 | Viewed by 1183

Abstract

Steviol and isosteviol were prepared from the commercially available sweetener stevioside and converted into lipophilic F16 hybrids. Their cytotoxicity was determined in SRB assays and showed to depend on both the substitution pattern of the aromatic substituent as well as on the spacer length. Therefore, compound 25 held an IC₅₀ (A2780) of 180 nM, thus surpassing the activity of comparable rhodamine hybrids. Several of the compounds were also able to overcome drug resistance in the A2780/A2780cis model. Extra staining experiments showed a similar subcellular accumulation pattern of the F16 hybrids as a well-established mitocan, hence proving preferential mitochondrial accumulation but also some other accumulation in other cellular areas. Full article

(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry II)

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12 pages, 1915 KiB

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Design, Synthesis and Antifungal Activities of Novel Pyrazole Analogues Containing the Aryl Trifluoromethoxy Group

by Tongchao Zhao, Yuyao Sun, Yufei Meng, Lifang Liu, Jingwen Dai, Guoan Yan, Xiaohong Pan, Xiong Guan, Liyan Song and Ran Lin

Molecules 2023, 28(17), 6279; https://doi.org/10.3390/molecules28176279 - 28 Aug 2023

Cited by 5 | Viewed by 1130

Abstract

On the basis of the three-component synthetic methodology developed by us, a total of twenty-six pyrazole compounds bearing aryl OCF₃ were designed and synthesized. Their chemical structures were characterized by ¹H and ¹³C nuclear magnetic resonance and high-resolution mass spectrometry. These compounds were evaluated systematically for antifungal activities in vitro against six plant pathogenic fungi by the mycelium growth rate method. Most of the compounds showed some activity against each of the fungi at 100 μg/mL. Compounds 1t and 1v exhibited higher activity against all the tested fungi, and 1v displayed the highest activity against F. graminearum with an EC₅₀ value of 0.0530 μM, which was comparable with commercial pyraclostrobin. Structure–activity relationship analysis showed that, with respect to the R₁ substituent, the straight chain or cycloalkyl ring moiety was a key structural moiety for the activity, and the R₂ substituent on the pyrazole ring could have significant effects on the activity. Simple and readily available pyrazoles with potent antifungal activity were obtained, which are ready for further elaboration to serve as a pharmacophore in new potential antifungal agents. Full article

(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry II)

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23 pages, 17693 KiB

Open AccessArticle

Design, Synthesis and Anticancer Evaluation of Nitroimidazole Radiosensitisers

by Lydia P. Liew, Avik Shome, Way W. Wong, Cho R. Hong, Kevin O. Hicks, Stephen M. F. Jamieson and Michael P. Hay

Molecules 2023, 28(11), 4457; https://doi.org/10.3390/molecules28114457 - 31 May 2023

Cited by 2 | Viewed by 1693

Abstract

The role of hypoxic tumour cells in resistance to radiotherapy, and in suppression of immune response, continues to endorse tumour hypoxia as a bona fide, yet largely untapped, drug target. Radiotherapy innovations such as stereotactic body radiotherapy herald new opportunities for classical oxygen-mimetic radiosensitisers. Only nimorazole is used clinically as a radiosensitiser, and there is a dearth of new radiosensitisers in development. In this report, we augment previous work to present new nitroimidazole alkylsulfonamides and we document their cytotoxicity and ability to radiosensitise anoxic tumour cells in vitro. We compare radiosensitisation with etanidazole and earlier nitroimidazole sulfonamide analogues and we identify 2-nitroimidazole and 5-nitroimidazole analogues with marked tumour radiosensitisation in ex vivo assays of surviving clonogens and with in vivo tumour growth inhibition. Full article

(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry II)

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15 pages, 3659 KiB

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Antibacterial Efficacy of N-(4-methylpyridin-2-yl) Thiophene-2-Carboxamide Analogues against Extended-Spectrum-β-Lactamase Producing Clinical Strain of Escherichia coli ST 131

by Gulraiz Ahmad, Aqsa Khalid, Muhammad Usman Qamar, Nasir Rasool, Malik Saadullah, Muhammad Bilal, Majed A. Bajaber, Ahmad J. Obaidullah, Hadil Faris Alotaibi and Jawaher M. Alotaibi

Molecules 2023, 28(7), 3118; https://doi.org/10.3390/molecules28073118 - 31 Mar 2023

Cited by 6 | Viewed by 1784

Abstract

Development in the fields of natural-product-derived and synthetic small molecules is in stark contrast to the ongoing demand for novel antimicrobials to treat life-threatening infections caused by extended-spectrum β-lactamase producing Escherichia coli (ESBL E. coli). Therefore, there is an interest in the antibacterial activities of synthesized N-(4-methylpyridin-2-yl) thiophene-2-carboxamides (4a–h) against ESBL-producing E. coli ST131 strains. A blood sample was obtained from a suspected septicemia patient and processed in the Bactec Alert system. The isolate’s identification and antibacterial profile were determined using the VITEK 2^® compact system. Multi-locus sequence typing of E. coli was conducted by identifying housekeeping genes, while ESBL phenotype detection was performed according to CLSI guidelines. Additionally, PCR was carried out to detect the blaCTX-M gene molecularly. Moreover, molecular docking studies of synthesized compounds (4a–h) demonstrated the binding pocket residues involved in the active site of the β-lactamase receptor of E. coli. The result confirmed the detection of E. coli ST131 from septicemia patients. The isolates were identified as ESBL producers carrying the blaCTX-M gene, which provided resistance against cephalosporins and beta-lactam inhibitors but sensitivity to carbapenems. Among the compounds tested, 4a and 4c exhibited high activity and demonstrated the best fit and interactions with the binding pocket of the β-lactamase enzyme. Interestingly, the maximum of the docking confirmations binds at a similar pocket region, further strengthening the importance of binding residues. Hence, the in vitro and molecular docking studies reflect the promising antibacterial effects of 4a and 4c compounds. Full article

(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry II)

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16 pages, 3089 KiB

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Comparative Study of the Lipophilicity of Selected Anti-Androgenic and Blood Uric Acid Lowering Compounds

by Dawid Wardecki, Małgorzata Dołowy, Katarzyna Bober-Majnusz and Josef Jampilek

Molecules 2023, 28(1), 166; https://doi.org/10.3390/molecules28010166 - 25 Dec 2022

Cited by 5 | Viewed by 1801

Abstract

This study aimed to evaluate the lipophilicity of a series substances lowering the concentration of uric acid in blood and anti-androgen drugs by thin-layer chromatography in reversed-phase systems (RP-TLC, RP-HPTLC) and computational methods. The chromatographic parameter of lipophilicity (R_MW) of tested compounds was determined on three stationary phases, i.e., RP18F₂₅₄, RP18WF₂₅₄ and RP2F₂₅₄, using ethanol–water, propan-2-ol-water and acetonitrile–water in various volume compositions as mobile phases. The chromatographic analysis led to determining the experimental value of the lipophilicity parameter for each of the tested compounds, including those for which the experimental value of the partition coefficient (logP_exp) as a measure of lipophilicity is not well described in available databases, such as febuxostat, oxypurinol, ailanthone, abiraterone and teriflunomide. The chromatographic parameters of lipophilicity were compared with the logP values obtained with various software packages, such as AClogP, AlogPs, AlogP, MlogP, XlogP2, XlogP3, ACD/logP and logP_KOWWIN. The obtained results indicate that, among selected chromatographic parameters of lipophilicity, both experimental and calculated logP values gave similar results, and these RP-TLC or RP-HPTLC systems can be successfully applied to estimate the lipophilicity of studied heterocyclic compounds belonging to two different pharmacological groups. This work also illustrates the similarity and difference existing between the tested compounds under study using the chemometric methods, such as principal component analysis (PCA) and cluster analysis (CA). In addition, a relatively new approach based on the sum of ranking differences (SRD) was used to compare the chromatographically obtained and theoretical lipophilicity descriptors of studied compounds. Full article

(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry II)

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16 pages, 11393 KiB

Open AccessArticle

5-(Indol-2-yl)pyrazolo[3,4-b]pyridines as a New Family of TASK-3 Channel Blockers: A Pharmacophore-Based Regioselective Synthesis

by David Ramírez, Melissa Mejia-Gutierrez, Braulio Insuasty, Susanne Rinné, Aytug K. Kiper, Magdalena Platzk, Thomas Müller, Niels Decher, Jairo Quiroga, Pedro De-la-Torre and Wendy González

Molecules 2021, 26(13), 3897; https://doi.org/10.3390/molecules26133897 - 25 Jun 2021

Cited by 7 | Viewed by 3696

Abstract

TASK channels belong to the two-pore-domain potassium (K_2P) channels subfamily. These channels modulate cellular excitability, input resistance, and response to synaptic stimulation. TASK-channel inhibition led to membrane depolarization. TASK-3 is expressed in different cancer cell types and neurons. Thus, the discovery of novel TASK-3 inhibitors makes these bioactive compounds very appealing to explore new cancer and neurological therapies. TASK-3 channel blockers are very limited to date, and only a few heterofused compounds have been reported in the literature. In this article, we combined a pharmacophore hypothesis with molecular docking to address for the first time the rational design, synthesis, and evaluation of 5-(indol-2-yl)pyrazolo[3,4-b]pyridines as a novel family of human TASK-3 channel blockers. Representative compounds of the synthesized library were assessed against TASK-3 using Fluorometric imaging plate reader—Membrane Potential assay (FMP). Inhibitory properties were validated using two-electrode voltage-clamp (TEVC) methods. We identified one active hit compound (MM-3b) with our systematic pipeline, exhibiting an IC₅₀ ≈ 30 μM. Molecular docking models suggest that compound MM-3b binds to TASK-3 at the bottom of the selectivity filter in the central cavity, similar to other described TASK-3 blockers such as A1899 and PK-THPP. Our in silico and experimental studies provide a new tool to predict and design novel TASK-3 channel blockers. Full article

(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry II)

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15 pages, 3758 KiB

Open AccessArticle

Synthesis, Antiprotozoal Activity, and Cheminformatic Analysis of 2-Phenyl-2H-Indazole Derivatives

by Karen Rodríguez-Villar, Lilián Yépez-Mulia, Miguel Cortés-Gines, Jacobo David Aguilera-Perdomo, Edgar A. Quintana-Salazar, Kevin Samael Olascoaga Del Angel, Francisco Cortés-Benítez, Juan Francisco Palacios-Espinosa, Olivia Soria-Arteche and Jaime Pérez-Villanueva

Molecules 2021, 26(8), 2145; https://doi.org/10.3390/molecules26082145 - 8 Apr 2021

Cited by 18 | Viewed by 3939

Abstract

Indazole is an important scaffold in medicinal chemistry. At present, the progress on synthetic methodologies has allowed the preparation of several new indazole derivatives with interesting pharmacological properties. Particularly, the antiprotozoal activity of indazole derivatives have been recently reported. Herein, a series of 22 indazole derivatives was synthesized and studied as antiprotozoals. The 2-phenyl-2H-indazole scaffold was accessed by a one-pot procedure, which includes a combination of ultrasound synthesis under neat conditions as well as Cadogan’s cyclization. Moreover, some compounds were derivatized to have an appropriate set to provide structure-activity relationships (SAR) information. Whereas the antiprotozoal activity of six of these compounds against E. histolytica, G. intestinalis, and T. vaginalis had been previously reported, the activity of the additional 16 compounds was evaluated against these same protozoa. The biological assays revealed structural features that favor the antiprotozoal activity against the three protozoans tested, e.g., electron withdrawing groups at the 2-phenyl ring. It is important to mention that the indazole derivatives possess strong antiprotozoal activity and are also characterized by a continuous SAR. Full article

(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry II)

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Review

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18 pages, 10217 KiB

Open AccessReview

Morpholine, Piperazine, and Piperidine Derivatives as Antidiabetic Agents

by Darya Zolotareva, Alexey Zazybin, Anuar Dauletbakov, Yelizaveta Belyankova, Beatriz Giner Parache, Saniya Tursynbek, Tulegen Seilkhanov and Anel Kairullinova

Molecules 2024, 29(13), 3043; https://doi.org/10.3390/molecules29133043 - 26 Jun 2024

Cited by 1 | Viewed by 1318

Abstract

Diabetes mellitus is a severe endocrine disease that affects more and more people every year. Modern medical chemistry sets itself the task of finding effective and safe drugs against diabetes. This review provides an overview of potential antidiabetic drugs based on three heterocyclic compounds, namely morpholine, piperazine, and piperidine. Studies have shown that compounds containing their moieties can be quite effective in vitro and in vivo for the treatment of diabetes and its consequences. Full article

(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry II)

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