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Special Issue "Heterocyclic Chemistry in Drug Design 2.0"

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A special issue of Scientia Pharmaceutica (ISSN 2218-0532).

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 18823

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Prof. Dr. Roman B. Lesyk

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Head of Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
Interests: medicinal chemistry; heterocyclic chemistry; organic synthesis; cancer biology; cancer cell line; pharmaceutical chemistry; anticancer compounds; apoptosis; QSAR
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Dear Colleagues,

Currently, the available chemical space includes more than 100 million organic compounds, mainly related to a limited set of classes and types. At the same time, modern drug design trends require the development of synthetic approaches to equally and diversely fill the chemical space as a source of drug-like structures. These trends have affected heterocyclic chemistry as the main "supplier" of drug-like molecules (all top 10 brand name small molecule drugs contain heterocyclic moieties), which stipulate strict requirements, both for bioactive compounds, as well as the methods of their synthesis. Thus, synthetic methods should provide a diversity of molecular architectonics, high chemo-, regio- and stereoselectivity, as well as atomic efficiency, in order to be ecologically and economically justified. The simultaneous implementation of these requirements is a rather difficult task, and research aimed at achieving a certain balance between them is relevant. As heterocycles are common fragments in the vast majority of marketed drugs, they obviously have a central role in modern drug design. It also should be mentioned that oxygen, sulfur, and, especially, nitrogen-containing rings, prevail among drug molecules.

In this Special Issue, we will focus on recent advances in heterocyclic chemistry in drug design.

Prof. Dr. Roman B. Lesyk
Guest Editor

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Keywords

heterocycles
diversity-oriented synthesis
regio-, stereo- and chemoselective synthesis
drug design
drug discovery
biological activity
SAR
lead generation

Published Papers (7 papers)

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Research

Open AccessArticle

3-[5-(1H-Indol-3-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl]-propionic Acid as a Potential Polypharmacological Agent

and

Sci. Pharm. 2023, 91(1), 13; https://doi.org/10.3390/scipharm91010013 - 02 Mar 2023

Cited by 1 | Viewed by 1398

Abstract

Searching for new types of biological activities among preliminarily identified hit compounds is a key challenge in modern medicinal chemistry. In our study, a previously studied 3-[5-(1H-indol-3-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl]-propionic acid (Les-6614) was screened for antimicrobial, antifungal, anti-allergic, and antitumor activities. Moreover, cytotoxicity, molecular docking, and SwissAdme online target screening were accomplished. It was determined that the Les-6614 has slight antimicrobial and antitumor activity. However, the studied compound decreased IgE levels in sensitized guinea pigs by 33–86% and reduced IgA, IgM, IL-2, and TNF-α, indicating anti-inflammatory and anti-allergic aactivities. According to the SwissADME web tool, target predictions for Les-6614 potentially have an affinity for lysosomal protective protein, Thromboxane-A synthase, and PPARγ. The molecular docking confirmed that the studied 2-thioxo-4-thiazolidinone derivative showed good bonding with LLP and TXAS, leading to stable protein–ligand complexes. Additionally, Les-6614 is a potential PPARγ modulator, which is important in the pathogenesis of allergy, cancer, and cardiovascular diseases. Full article

(This article belongs to the Special Issue Heterocyclic Chemistry in Drug Design 2.0)

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Open AccessArticle

Evaluation of 5-[(Z)-(4-nitrobenzylidene)]-2-(thiazol-2-ylimino)-4-thiazolidinone (Les-6222) as Potential Anticonvulsant Agent

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Sci. Pharm. 2022, 90(3), 56; https://doi.org/10.3390/scipharm90030056 - 19 Sep 2022

Cited by 2 | Viewed by 1803

Abstract

It was determined that the studied 5-[(Z)-(4-nitrobenzylidene)]-2-(thiazol-2-ylimino)-4-thiazolidinone (Les-6222) affects the cyclooxygenase pathway of the arachidonic acid cascade, the markers of damage to neurons on models of PTZ kindling. In the model of chronic epileptogenesis in mice (pentylenetetrazole kindling), a 4-thiazolidinone derivative showed high anticonvulsant activity, which is weaker than the effect of sodium valproate and higher than Celecoxib. The mentioned compound has a pronounced anti-inflammatory effect in the brain on the background of the PTZ kindling, reliably inhibiting COX-1 and COX-2. The predominant inhibition of COX-2 by 44.5% indicates this enzyme’s high selectivity of Les-6222. According to the molecular docking study results, the studied compound revealed the properties of COX-1/COX-2 inhibitor and especially 5-LOX/FLAP. The decreasing content of 8-isoprostane in the brain of mice of the Les-6222 group indicates a beneficial effect on cell membranes in the background of oxidative stress during the long-term administration of PTZ. In addition, Les-6222 significantly decreased the content of neuron-specific enolase, indicating neuroprotective properties in the background of chronic epileptogenesis. The obtained results experimentally substantiate the feasibility of further developing Les-6222 as a promising anticonvulsant agent. Full article

(This article belongs to the Special Issue Heterocyclic Chemistry in Drug Design 2.0)

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Open AccessArticle

2D-QSAR and CoMFA Models for Antitubercular Activity of Scalarane-Type Sesterterpenes

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Sci. Pharm. 2022, 90(3), 47; https://doi.org/10.3390/scipharm90030047 - 15 Aug 2022

Viewed by 1370

Abstract

A series of scalarane sesterterpenes were prepared using heteronemin (1) as a primary precursor. Combined with the scalarane derivatives obtained from natural sources, a total of 22 antitubercular scalaranes were used to build QSAR models based in the 2D-QSAR and CoMFA approaches. Both models indicated the influences of substitutions in the vicinity of C-12 and C-16 of the scalaranes. A 2D-QSAR model suggested the necessity of hydrophilic functionalities on the peripherals with hydrophobic cores, and the lowering steric repulsion to improve the potential energy. This was complemented by the pictorial CoMFA model, which indicated the importance of the positive electrostatic with shortened steric extension crowning over C-12 and the lengthy negative functionalities extended from C-16. Full article

(This article belongs to the Special Issue Heterocyclic Chemistry in Drug Design 2.0)

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Open AccessArticle

The Search for New Antibacterial Agents among 1,2,3-Triazole Functionalized Ciprofloxacin and Norfloxacin Hybrids: Synthesis, Docking Studies, and Biological Activity Evaluation

Halyna Hryhoriv

Illia Mariutsa

Sergiy M. Kovalenko

Victoriya Georgiyants

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Sci. Pharm. 2022, 90(1), 2; https://doi.org/10.3390/scipharm90010002 - 22 Dec 2021

Cited by 8 | Viewed by 3078

Abstract

Among all modern antibiotics, fluoroquinolones are well known for their broad spectrums of activity and efficiency toward microorganisms and viruses. However, antibiotic resistance is still a problem, which has encouraged medicinal chemists to modify the initial structures in order to combat resistant strains. Our current work is aimed at synthesizing novel hybrid derivatives of ciprofloxacin and norfloxacin and applying docking studies and biological activity evaluations in order to find active promising molecules. We succeeded in the development of a synthetic method towards 1,2,3-triazole-substituted ciprofloxacin and norfloxacin derivatives. The structure and purity of the obtained compounds were confirmed by ¹H NMR, ¹³C NMR, ¹⁹F NMR, LC/MS, UV-, IR- spectroscopy. Docking studies, together with in vitro research against Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, Bacillus subtilis ATCC 6633, Pseudomonas aeruginosa ATCC 27853, Candida albicans NCTC 885-653 revealed compounds in which activity exceeded the initial molecules. Full article

(This article belongs to the Special Issue Heterocyclic Chemistry in Drug Design 2.0)

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Open AccessArticle

Synthesis and Biological Activity Evaluation of Novel 5-Methyl-7-phenyl-3H-thiazolo[4,5-b]pyridin-2-ones

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Sci. Pharm. 2021, 89(4), 52; https://doi.org/10.3390/scipharm89040052 - 25 Nov 2021

Cited by 1 | Viewed by 3296

Abstract

A series of 5-methyl-7-phenyl-3H-thiazolo[4,5-b]pyridin-2-ones has been designed, synthesized, and characterized by spectral data. Target compounds were screened for their antimicrobial activity against some pathogenic bacteria and fungi, and most of them showed moderate activity, especially compound 3g, which displayed the potent inhibitory effect against Pseudomonas aeruginosa and Escherichia coli with MIC value of 0.21 μM. The active thiazolopyridine derivatives 3c, 3f, and 3g were screened for their cytotoxicity effects on HaCat, Balb/c 3T3 cells using MTT assay, which revealed promising results. In silico assessment for compounds 3c, 3f, and 3g also revealed suitable drug-like parameters and ADME properties. The binding interactions of the most active compound 3g were performed through molecular docking against MurD and DNA gyrase, with binding energies and an inhibitory constant compared to the reference drug ciprofloxacin. The tested thiazolo[4,5-b]pyridines constitute an exciting background for the further development of new synthetic antimicrobial agents. Full article

(This article belongs to the Special Issue Heterocyclic Chemistry in Drug Design 2.0)

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Open AccessArticle

Design, Synthesis and In Vitro Antimicrobial Activity of 6-(1H-Benzimidazol-2-yl)-3,5-dimethyl-4-oxo-2-thio-3,4-dihydrothieno[2,3-d]pyrimidines

Sergiy V. Vlasov

Olena D. Vlasova

Hanna I. Severina

Konstantin Yu. Krolenko

Oleksandr V. Borysov

Amjad Ibrahim M. Abu Sharkh

Vitaliy S. Vlasov

and

Victoriya A. Georgiyants

Sci. Pharm. 2021, 89(4), 49; https://doi.org/10.3390/scipharm89040049 - 18 Nov 2021

Cited by 4 | Viewed by 2968

Abstract

The rapid development in bacterial resistance to many groups of known antibiotics forces the researchers to discover antibacterial drug candidates with previously unknown mechanisms of action, one of the most relevant being the inhibition of tRNA (Guanine37-N1)-methyltransferase (TrmD). The discovery of selective TrmD inhibitors in the series of carboxamide derivatives of thienopyrimidines became a background for further modification of the similar structures aimed at the development of promising antibacterial agents. As part of this research, we carried out the construction of heterocyclic hybrids bearing the moieties of thieno[2,3-d]pyrimidine and benzimidazole starting from 3,5-dimethyl-4-oxo-2-thioxo-1H-thieno[2,3-d]pyrimidine-6-carboxylic acid, which was used as the pivotal intermediate. The hybrid molecule of 6-(1H-benzimidazol-2-yl)-3,5-dimethyl-2-thioxo-1H-thieno[2,3-d]pyrimidin-4-one prepared via condensation of the carboxylic acid with ortho-phenylenediamine was further alkylated with aryl/hetaryl chloroacetamides and benzyl chloride to produce the series of S-alkyl derivatives. The results of molecular docking studies for the obtained series of S-alkyl benzimidazole-thienopyrimidines showed their high affinity to the TrmD isolated from the P. aeruginosa. The results of antimicrobial activity screening revealed the antimicrobial properties for all of the studied molecules against both Gram-positive and Gram-negative bacteria and the Candida albicans fungal strain. The highest antimicrobial activity was determined for 2-{[6-(1H-benzimidazol-2-yl)-3,5-dimethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl]thio}-N-(4-isopropylphenyl)acetamide, which also had the highest affinity to the TrmD inhibitor’s binding site according to the docking studies results. Full article

(This article belongs to the Special Issue Heterocyclic Chemistry in Drug Design 2.0)

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Open AccessArticle

Stability Enhancement and Skin Permeation Application of Nicotine by Forming Inclusion Complex with β-Cyclodextrin and Methyl-β-Cyclodextrin

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Sci. Pharm. 2021, 89(4), 43; https://doi.org/10.3390/scipharm89040043 - 28 Sep 2021

Cited by 2 | Viewed by 3638

Abstract

Nicotine is widely used in pharmaceutical industries, especially for smoking cessation in the form of transdermal patches. Nicotine gel in the patches has limitations from nicotine instability and high volatility. Thus, a nicotine preservation technique is needed. In this study, a nicotine encapsulation process using methyl-β-cyclodextrin (MβCD) is investigated and compared with β-cyclodextrin (βCD) to evaluate the preservation and skin permeation of nicotine. The M06-2X/6-31G(d,p) density functional theory calculations indicate a 1:1 host–guest molar ratio for the inclusion complex of nicotine with βCD and MβCD, which have been validated by experimental studies. The encapsulation efficiencies of βCD and MβCD to encapsulate nicotine are 59.96% and 63.76%, respectively. The preservation study of the inclusion complexes compared to pure nicotine shows a stability improvement of nicotine after being encapsulated. After 21 days, the percentages of the nicotine/βCD and nicotine/MβCD inclusion complexes that remain are 89.32% and 76.22%, while only 65.56% of pure nicotine remains. Besides the one-hour skin permeation tests, the amounts of nicotine permeated through pig skin from the nicotine/βCD and nicotine/MβCD inclusion complex gels are 14 and 10 times as much as the pure nicotine gel, respectively. Therefore, the encapsulation of nicotine with βCD and MβCD can be used to enhance the stability and skin permeation application of nicotine-containing products. Full article

(This article belongs to the Special Issue Heterocyclic Chemistry in Drug Design 2.0)

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