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Synthesis of Heterocyclic Compounds via Cycloadditions: Applications in Medicinal Chemistry

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

Deadline for manuscript submissions: closed (31 October 2024) | Viewed by 6329

Special Issue Editors


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Guest Editor
Department of Chemistry, Indiana University, Bloomington, IN 47405, USA
Interests: flow chemistry; organic synthesis; total synthesis; cycloadditions; heterocyclics; carbohydrates; medicinal chemistry
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Guest Editor
School of Chemistry, University of KwaZulu-Natal, Durban, South Africa
Interests: synthetic methodology; computational chemistry and molecular modelling; pharmacophore design; medicinal Chemistry; ligand–protein interactions; peptide folding; docking
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Department of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, The Medical University of Silesia in Katowice, Jagiellońska 4, 41-200 Sosnowiec, Poland
Interests: organic synthesis; heterocycles; dipyridothiazines; structural analysis; lipophylicity; SAR
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Heterocyclic compounds, also known as heterocycles, are the most common constituents of many pharmaceutical drugs. They are the major class of organic chemical compounds characterized by the notion that some or all of the atoms are joined in rings containing at least one atom other than carbon. Heterocyclic compounds are used in agrochemicals and pharmaceutical industries. They are used as starting materials in the synthesis of organic compounds and used in corrosion inhibitors, sanitizers, antiordinates, developers, pesticides, dyes and plastics.

The hybridization of two heterocyclic scaffolds forms a single compound, with the potential to have antibacterial, antimalarial, antitubercular and anticancer activity. Active functional groups like hydroxyl, methyl, carbonyl, carboxyl, amino, phosphate, etc., are often used in the synthetic strategy to join the two scaffolds together. Further, heterocycles including beta-lactams, pyrimidinones, 1,3,4-thiadiazoles and their molecular hybrids with different pharmacophoric assemblies following the hetero Diels–Alder methodology are known for their biological activities under in vitro conditions. Understanding how the rings of this class of antibiotics are formed is crucial to developing new treatments to combat antibiotic resistance using cycloadditions.

Cycloaddition reactions are considered among the most powerful bond-forming reactions in organic synthesis because of their ability to form many bonds in one step and the potential to generate several stereogenic centers at the same time with predictable stereochemical outcomes. Cycloaddition reactions are applied to the synthesis of anticancer compounds by making use of classical Diels–Alder and their hetero version for the design and synthesis of compounds that were tested for their antiproliferative activities as well as apoptosis. 1,3-dipolar cycloaddition reactions of selected 1,3-dipoles, such as azides, nitrones, nitrile oxides, nitrile imines and azomethine ylides, also have a major application in the preparation of key intermediates for anticancer synthesis. In addition, the products obtained from the pericyclic reaction approaches are important for anticancer activities and the relevant biological data are highlighted.

Medicinal chemistry remains the most valuable science and plays the most critical role in the drug-development process. It acts as the backbone of the drug-discovery framework that provides a comprehensive understanding of the underlying principles of drug action and behavior within the body, which is fundamental to today's pharmaceutical care and patient counseling.

This Special Issue targets the public understanding of the chemistry behind heterocycles for pharmaceutical applications. Preference will be given to articles, which focus on target-based design strategies, organic synthesis, in vitro assays, enzymatic assays that confirm the target, in vivo experiments, SAR, and docking that improves the understanding of drug design and action. The targets are including but are not limited to: Kinases, DNA topoisomerases, Tubulin, and HDAC.

Dr. Lalitha Gummidi
Dr. Parvesh Singh
Prof. Dr. Beata Morak-Młodawska
Guest Editors

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Keywords

  • heterocycles
  • synthesis
  • anticancer
  • in vitro
  • cycloadditions
  • drug

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Published Papers (4 papers)

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Research

14 pages, 706 KiB  
Article
Synthesis, Anticancer Activity, and Molecular Docking of New 1,2,3-Triazole Linked Tetrahydrocurcumin Derivatives
by Meitao Duan, Ahmed Mahal, Anas Alkouri, Chen Wang, Zhiqiang Zhang, Jungang Ren and Ahmad J. Obaidullah
Molecules 2024, 29(13), 3010; https://doi.org/10.3390/molecules29133010 - 25 Jun 2024
Cited by 1 | Viewed by 1409
Abstract
Cancer is one of the deadliest diseases to humanity. There is significant progress in treating this disease, but developing some drugs that can fight this disease remains a challenge in the field of medical research. Thirteen new 1,2,3-triazole linked tetrahydrocurcumin derivatives were synthesized [...] Read more.
Cancer is one of the deadliest diseases to humanity. There is significant progress in treating this disease, but developing some drugs that can fight this disease remains a challenge in the field of medical research. Thirteen new 1,2,3-triazole linked tetrahydrocurcumin derivatives were synthesized by click reaction, including a 1,3-dipolar cycloaddition reaction of tetrahydrocurcumin baring mono-alkyne with azides in good yields, and their in vitro anticancer activity against four cancer cell lines, including human cervical carcinoma (HeLa), human lung adenocarcinoma (A549), human hepatoma carcinoma (HepG2), and human colon carcinoma (HCT-116) were investigated using MTT(3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetraz-olium bromide) assay. The newly synthesized compounds had their structures identified using NMR HRMS and IR techniques. Some of prepared compounds, including compounds 4g and 4k, showed potent cytotoxic activity against four cancer cell lines compared to the positive control of cisplatin and tetrahydrocurcumin. Compound 4g exhibited anticancer activity with a IC50 value of 1.09 ± 0.17 μM against human colon carcinoma HCT-116 and 45.16 ± 0.92 μM against A549 cell lines compared to the positive controls of tetrahydrocurcumin and cisplatin. Moreover, further biological examination in HCT-116 cells showed that compound 4g can arrest the cell cycle at the G1 phase. A docking study revealed that the potential mechanism by which 4g exerts its anti-colon cancer effect may be through inhabiting the binding of APC–Asef. Compound 4g can be used as a promising lead for further exploration of potential anticancer agents. Full article
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10 pages, 2042 KiB  
Article
Practical Synthesis of 7-Bromo-4-chloro-1H-indazol-3-amine: An Important Intermediate to Lenacapavir
by Naeem Asad, Michael Lyons, Shirley Muniz Machado Rodrigues, Justina M. Burns, Thomas D. Roper, G. Michael Laidlaw, Saeed Ahmad, B. Frank Gupton, Douglas Klumpp and Limei Jin
Molecules 2024, 29(12), 2705; https://doi.org/10.3390/molecules29122705 - 7 Jun 2024
Viewed by 1157
Abstract
7-Bromo-4-chloro-1H-indazol-3-amine is a heterocyclic fragment used in the synthesis of Lenacapavir, a potent capsid inhibitor for the treatment of HIV-1 infections. In this manuscript, we describe a new approach to synthesizing 7-bromo-4-chloro-1H-indazol-3-amine from inexpensive 2,6-dichlorobenzonitrile. This synthetic method utilizes [...] Read more.
7-Bromo-4-chloro-1H-indazol-3-amine is a heterocyclic fragment used in the synthesis of Lenacapavir, a potent capsid inhibitor for the treatment of HIV-1 infections. In this manuscript, we describe a new approach to synthesizing 7-bromo-4-chloro-1H-indazol-3-amine from inexpensive 2,6-dichlorobenzonitrile. This synthetic method utilizes a two-step sequence including regioselective bromination and heterocycle formation with hydrazine to give the desired product in an overall isolated yield of 38–45%. The new protocol has been successfully demonstrated on hundred-gram scales without the need for column chromatography purification. This new synthesis provides a potential economical route to the large-scale production of this heterocyclic fragment of Lenacapavir. Full article
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13 pages, 2370 KiB  
Article
In Silico and In Vitro Studies of 4-Hydroxycoumarin-Based Heterocyclic Enamines as Potential Anti-Tumor Agents
by Mediha Assad, Rizwan Nasir Paracha, Abu Bakar Siddique, Muhammad Ashraf Shaheen, Nadeem Ahmad, Muhammad Mustaqeem, Fariha Kanwal, Muhammad Zia Ul Mustafa, Muhammad Fayyaz ur Rehman, Sumaya Fatima and Changrui Lu
Molecules 2023, 28(15), 5828; https://doi.org/10.3390/molecules28155828 - 2 Aug 2023
Cited by 1 | Viewed by 1392
Abstract
The present study reports the one-step synthesis of several 3-formyl-4-hydroxycouramin-derived enamines (4a4i) in good yields (65–94%). The characterization of the synthesized compounds was carried out via advanced analytical and spectroscopic techniques, such as melting point, electron impact mass spectrometry [...] Read more.
The present study reports the one-step synthesis of several 3-formyl-4-hydroxycouramin-derived enamines (4a4i) in good yields (65–94%). The characterization of the synthesized compounds was carried out via advanced analytical and spectroscopic techniques, such as melting point, electron impact mass spectrometry (EI-MS), 1H-NMR, 13C-NMR, elemental analysis, FTIR, and UV-Visible spectroscopy. The reaction conditions were optimized, and the maximum yield was obtained at 3–4 h of reflux of the reactants, using 2-butanol as a solvent. The potato disc tumor assay was used to assess Agrobacterium tumefaciens-induced tumors to evaluate the anti-tumor activities of compounds (4a4i), using Vinblastine as a standard drug. The compound 4g showed the lowest IC50 value (1.12 ± 0.2), which is even better than standard Vinblastine (IC50 7.5 ± 0.6). For further insight into their drug actions, an in silico docking of the compounds was also carried out against the CDK-8 protein. The binding energy values of compounds were found to agree with the experimental results. The compounds 4g and 4h showed the best affinities toward protein, with a binding energy value of −6.8 kcal/mol. Full article
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11 pages, 2336 KiB  
Article
Full Regio- and Stereoselective Protocol for the Synthesis of New Nicotinoids via Cycloaddition Processes with the Participation of Trans-Substituted Nitroethenes: Comprehensive Experimental and MEDT Study
by Jowita Kras, Przemysław Woliński, Roman Nagatsky, Oleg M. Demchuk and Radomir Jasiński
Molecules 2023, 28(8), 3535; https://doi.org/10.3390/molecules28083535 - 17 Apr 2023
Cited by 2 | Viewed by 1172
Abstract
[3 + 2] Cycloaddition reactions with the participation of Z-C-(3-pyridyl)-N-methylnitrone and series of E-2-R-nitroethenes were both experimentally and theoretically explored in the framework of Molecular Electron Density Theory. It was found that all considered processes are realized under mild [...] Read more.
[3 + 2] Cycloaddition reactions with the participation of Z-C-(3-pyridyl)-N-methylnitrone and series of E-2-R-nitroethenes were both experimentally and theoretically explored in the framework of Molecular Electron Density Theory. It was found that all considered processes are realized under mild conditions and in full regio- and stereocontrol. The ELF analysis additionally showed that the studied reaction proceeds by a two-stage, one-step mechanism. Full article
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