Novel Heterocyclic Compounds for Drug Discovery

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

Deadline for manuscript submissions: closed (26 October 2023) | Viewed by 9048

Special Issue Editor


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Guest Editor
Department of Theoretical and Applied Chemistry, South Ural State University, Lenin Prospect 76, 454080 Chelyabinsk, Russia
Interests: organic synthesis; heterocyclic chemistry in drug discovery; medicinal chemistry; new synthetic methodologies; synthesis of new heterocyclic compounds
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Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute a full article, short communication, or review article to a Special Issue entitled “Novel Heterocyclic Compounds in Drug Development”. The Special Issue aims to cover the most recent advances in organic chemistry and newly heterocyclic compounds and their potential role in medicinal chemistry.

Heterocyclic compounds are one of the largest and most varied classes of organic chemistry that are widespread in many natural compounds, with special attention in drug development. The heterocycle is a major class of organic compounds characterized by the presence of rings containing at least one atom of an element other than a carbon atom. The presence of the heteroatoms of nitrogen (N), oxygen (O), or sulfur (S) gives heterocyclic compounds distinct physical and chemical properties from those of other organic compounds.

Heterocyclic rings play an important role in biochemical processes, as they are one of the key elements of DNA, RNA, and coenzymes. They are present in many different pharmaceutical drugs exhibiting a broad range of biological activities including antimicrobial, anticancer, anticonvulsant, anti-HIV, anti-inflammatory, antioxidants, analgesic, antitubercular, and antimalarial agents.

We invite manuscript submissions of original research articles and reviews that discuss new bioactive heterocycle-containing compounds and their applications in medicinal chemistry, including design; synthesis; reactions; characterization of new chemical entities with therapeutic potential; structure elucidation; molecular modeling, and structure–activity relationships; pharmacokinetics investigation for new drugs; and the development of assays to assess therapeutic efficacy.

Dr. Youness El Bakri
Guest Editor

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Keywords

  • drug discovery
  • new heterocyclic compounds
  • new synthetic methodologies
  • pharmaceutics
  • medicinal agents synthesis
  • biochemical mechanism
  • natural product synthesis
  • natural products including pharmacological products

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Published Papers (4 papers)

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Research

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19 pages, 4232 KiB  
Article
In Vitro and In Silico Evaluation of Antiproliferative Activity of New Isoxazolidine Derivatives Targeting EGFR: Design, Synthesis, Cell Cycle Analysis, and Apoptotic Inducers
by Fahad Alminderej, Siwar Ghannay, Mohamed O. Elsamani, Fahad Alhawday, Abuzar E. A. E. Albadri, Serag Eldin I. Elbehairi, Mohammad Y. Alfaifi, Adel Kadri and Kaïss Aouadi
Pharmaceuticals 2023, 16(7), 1025; https://doi.org/10.3390/ph16071025 - 19 Jul 2023
Cited by 7 | Viewed by 2405
Abstract
A series of novel enantiopure isoxazolidine derivatives were synthesized and evaluated for their anticancer activities against three human cancer cell lines such as human breast carcinoma (MCF-7), human lung adenocarcinoma (A-549), and human ovarian carcinoma (SKOV3) by employing MTT assay. The synthesized compounds [...] Read more.
A series of novel enantiopure isoxazolidine derivatives were synthesized and evaluated for their anticancer activities against three human cancer cell lines such as human breast carcinoma (MCF-7), human lung adenocarcinoma (A-549), and human ovarian carcinoma (SKOV3) by employing MTT assay. The synthesized compounds were characterized by NMR and elemental analysis. Results revealed that all the synthesized compounds displayed significant inhibition towards the tested cell lines. Among them, 2g and 2f, which differ only by the presence of an ester group at the C-3 position and small EDG (methyl) at the C-5 position of the phenyl ring (2g), were the most active derivatives in attenuating the growth of the three cells in a dose-dependent manner. The IC50 for 2g were 17.7 ± 1 µM (MCF-7), 12.1 ± 1.1 µM (A-549), and 13.9 ± 0.7 µM (SKOV3), and for 2f were 9.7 ± 1.3µM (MCF-7), 9.7 ± 0.7µM (A-549), and 6.5 ± 0.9µM (SKOV3), respectively, which were comparable to the standard drug, doxorubicin. The enzymatic inhibition of 2f and 2g against EGFR afforded good inhibitory activity with IC50 of 0.298 ± 0.007 μM and 0.484 ± 0.01 µM, respectively, close to the positive control, Afatinib. Compound 2f arrested the cell cycle in the S phase in MCF-7 and SKOV3 cells, and in the G2/M phase in the A549 cell; however, 2g induced G0/G1 phase cell cycle arrest, and inhibited the progression of the three cancer cells, together with significant apoptotic effects. The docking study of compounds 2f and 2g into EGFR ATP-active site revealed that it fits nicely with good binding affinity. The pharmacokinetic and drug-likeness scores revealed notable lead-like properties. At 100 ns, the dynamic simulation investigation revealed high conformational stability in the EGFR binding cavity. Full article
(This article belongs to the Special Issue Novel Heterocyclic Compounds for Drug Discovery)
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30 pages, 3655 KiB  
Article
Exploring Pyrrolo-Fused Heterocycles as Promising Anticancer Agents: An Integrated Synthetic, Biological, and Computational Approach
by Roxana-Maria Amărandi, Maria-Cristina Al-Matarneh, Lăcrămioara Popovici, Catalina Ionica Ciobanu, Andrei Neamțu, Ionel I. Mangalagiu and Ramona Danac
Pharmaceuticals 2023, 16(6), 865; https://doi.org/10.3390/ph16060865 - 11 Jun 2023
Cited by 4 | Viewed by 1650
Abstract
Five new series of pyrrolo-fused heterocycles were designed through a scaffold hybridization strategy as analogs of the well-known microtubule inhibitor phenstatin. Compounds were synthesized using the 1,3-dipolar cycloaddition of cycloimmonium N-ylides to ethyl propiolate as a key step. Selected compounds were then evaluated [...] Read more.
Five new series of pyrrolo-fused heterocycles were designed through a scaffold hybridization strategy as analogs of the well-known microtubule inhibitor phenstatin. Compounds were synthesized using the 1,3-dipolar cycloaddition of cycloimmonium N-ylides to ethyl propiolate as a key step. Selected compounds were then evaluated for anticancer activity and ability to inhibit tubulin polymerization in vitro. Notably, pyrrolo[1,2-a]quinoline 10a was active on most tested cell lines, performing better than control phenstatin in several cases, most notably on renal cancer cell line A498 (GI50 27 nM), while inhibiting tubulin polymerization in vitro. In addition, this compound was predicted to have a promising ADMET profile. The molecular details of the interaction between compound 10a and tubulin were investigated through in silico docking experiments, followed by molecular dynamics simulations and configurational entropy calculations. Of note, we found that some of the initially predicted interactions from docking experiments were not stable during molecular dynamics simulations, but that configurational entropy loss was similar in all three cases. Our results suggest that for compound 10a, docking experiments alone are not sufficient for the adequate description of interaction details in terms of target binding, which makes subsequent scaffold optimization more difficult and ultimately hinders drug design. Taken together, these results could help shape novel potent antiproliferative compounds with pyrrolo-fused heterocyclic cores, especially from an in silico methodological perspective. Full article
(This article belongs to the Special Issue Novel Heterocyclic Compounds for Drug Discovery)
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19 pages, 2026 KiB  
Article
7-Chloroquinolinehydrazones as First-in-Class Anticancer Experimental Drugs in the NCI-60 Screen among Different Investigated Series of Aryl, Quinoline, Pyridine, Benzothiazole and Imidazolehydrazones
by Georgiana Negru (Apostol), Alina Ghinet and Elena Bîcu
Pharmaceuticals 2023, 16(5), 691; https://doi.org/10.3390/ph16050691 - 3 May 2023
Viewed by 1694
Abstract
In the context of a continuously increasing global cancer risk, the search for new effective and affordable anticancer drugs remains a constant demand. This study describes chemical experimental drugs able to destroy cancer cells by arresting their growth. New hydrazones with quinoline, pyridine, [...] Read more.
In the context of a continuously increasing global cancer risk, the search for new effective and affordable anticancer drugs remains a constant demand. This study describes chemical experimental drugs able to destroy cancer cells by arresting their growth. New hydrazones with quinoline, pyridine, benzothiazole and imidazole moieties have been synthesized and evaluated for their cytotoxic potential against 60 cancer cell lines. 7-Chloroquinolinehydrazones were the most active in the current study and exhibited good cytotoxic activity with submicromolar GI50 values on a large panel of cell lines from nine tumor types (leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer). This study provided consistent structure-activity relationships in this series of experimental antitumor compounds. Full article
(This article belongs to the Special Issue Novel Heterocyclic Compounds for Drug Discovery)
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Review

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39 pages, 11167 KiB  
Review
Quinoxaline 1,4-Dioxides: Advances in Chemistry and Chemotherapeutic Drug Development
by Galina I. Buravchenko and Andrey E. Shchekotikhin
Pharmaceuticals 2023, 16(8), 1174; https://doi.org/10.3390/ph16081174 - 17 Aug 2023
Cited by 4 | Viewed by 2388
Abstract
N-Oxides of heterocyclic compounds are the focus of medical chemistry due to their diverse biological properties. The high reactivity and tendency to undergo various rearrangements have piqued the interest of synthetic chemists in heterocycles with N-oxide fragments. Quinoxaline 1,4-dioxides are an [...] Read more.
N-Oxides of heterocyclic compounds are the focus of medical chemistry due to their diverse biological properties. The high reactivity and tendency to undergo various rearrangements have piqued the interest of synthetic chemists in heterocycles with N-oxide fragments. Quinoxaline 1,4-dioxides are an example of an important class of heterocyclic N-oxides, whose wide range of biological activity determines the prospects of their practical use in the development of drugs of various pharmaceutical groups. Derivatives from this series have found application in the clinic as antibacterial drugs and are used in agriculture. Quinoxaline 1,4-dioxides present a promising class for the development of new drugs targeting bacterial infections, oncological diseases, malaria, trypanosomiasis, leishmaniasis, and amoebiasis. The review considers the most important methods for the synthesis and key directions in the chemical modification of quinoxaline 1,4-dioxide derivatives, analyzes their biological properties, and evaluates the prospects for the practical application of the most interesting compounds. Full article
(This article belongs to the Special Issue Novel Heterocyclic Compounds for Drug Discovery)
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