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Design, Synthesis and Biological Evaluation of Heterocyclic Compounds
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Design, Synthesis and Biological Evaluation of Heterocyclic Compounds

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

Deadline for manuscript submissions: closed (31 January 2025) | Viewed by 9252

Special Issue Editor

Prof. Dr. Sotiris S. Nikolaropoulos

E-Mail Website
Guest Editor
Laboratory of Medicinal Chemistry, Department of Pharmacy, University of Patras, GR-26500 Patras, Greece
Interests: heterocycles; QSAR; synthesis of organic compounds; rational design; heterocyclic steroids; aromatic compounds; virtual screening

Special Issue Information

Dear Colleagues,

Heterocycles tend to become independently organized into a variety of functional scaffolds and to socialize with other partner molecules, forming small biomolecular complexes or large assemblies, in various intersections of biological pathways. Heterocycles’ architecture, rigidity and interaction determine the fate of a variety of biological events. Understanding the functional role of the heterocycles and their derivatives is strongly coupled to atomic-level insights into their structure and specificity.

The research activities of many groups encompass the study of the design, synthesis, structure analysis and biological profiles of heterocycles, both in vivo and in vitro.

Prof. Dr. Sotiris S. Nikolaropoulos
Guest Editor

Manuscript Submission Information

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Keywords

  • heterocycles
  • heterocyclic chemistry
  • biological profile
  • in silico design
  • natural products
  • pharmaceuticals
  • C–N/C–C bond formation

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Published Papers (6 papers)

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Research

26 pages, 5819 KiB  
Article
Synthesis and Structural Analysis of New (−)-Cytisine Squaramides
by Anna K. Przybył, Jan Janczak and Adam Huczyński
Molecules 2025, 30(5), 1135; https://doi.org/10.3390/molecules30051135 - 1 Mar 2025
Viewed by 639
Abstract
Derivatives of squaric acid are valuable building blocks with promising applications in the investigation of various bioactivities. In this study, we focus on squaramides functionalized with the (−)-cytisine moiety, an alkaloid known for its bioactivity as a nicotinic acetylcholine receptor agonist and its [...] Read more.
Derivatives of squaric acid are valuable building blocks with promising applications in the investigation of various bioactivities. In this study, we focus on squaramides functionalized with the (−)-cytisine moiety, an alkaloid known for its bioactivity as a nicotinic acetylcholine receptor agonist and its application in nicotine addiction treatment. Reactions of cytisine-monosquarate with several amines, such as ammonia, propargylamine, and morpholine, led to the formation of novel conjugates of cytisine-squaramides. Additionally, squaramide containing two cytisine moieties was synthesized via the reaction of diethyl squarate with cytisine at a 1:2 molar ratio. All obtained squaramides were thoroughly characterized by MS, FT-IR, and NMR methods and by single-crystal X-ray diffraction analysis. To gain deeper insights into their structural properties and intermolecular interactions, geometry optimizations were performed using DFT calculations, complemented with 3D molecular electrostatic potential maps. Full article
(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Heterocyclic Compounds)
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13 pages, 1666 KiB  
Article
The Use of a Penta-Deuterophenyl Substituent to Improve the Metabolic Stability of a Tyrosine Kinase Inhibitor
by Júlia Dulsat, Raimon Puig de la Bellacasa and José I. Borrell
Molecules 2024, 29(24), 6042; https://doi.org/10.3390/molecules29246042 - 22 Dec 2024
Viewed by 881
Abstract
In cases in which a rapid metabolism is the cause of an unfavorable pharmacokinetic profile, it is important to determine the Sites of Metabolism (SoMs) of a molecule to introduce the necessary modifications to improve the stability of the compound. The substitution of [...] Read more.
In cases in which a rapid metabolism is the cause of an unfavorable pharmacokinetic profile, it is important to determine the Sites of Metabolism (SoMs) of a molecule to introduce the necessary modifications to improve the stability of the compound. The substitution of hydrogen atoms by deuterium atoms has been proposed to ameliorate such properties due to the greater stability of the C-D bonds. IQS016, bearing a 2-phenylamino substituent, is a compound previously described by our group with good biological activity as a discoidin domain receptor (DDR2) inhibitor but suffers from low metabolic stability determined in a test with rat-liver microsomes (less than 50% of the initial compound after 60 min). We have obtained the corresponding 2-(penta-deuterophenyl) analog (IQS016-d5) from aniline-2,3,4,5,6-d5 showing that it has a better metabolic stability than IQS016 and a higher inhibitory effect on isolated tyrosine kinase receptors but not a better 2D in vitro effect. Full article
(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Heterocyclic Compounds)
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14 pages, 428 KiB  
Article
Exploring 4,7-Disubstituted Pyrimido[4,5-d]pyrimidines as Antiviral and Anticancer Agents
by Eleftheria A. Georgiou, Konstantinos Paraskevas, Christina Koutra, Leentje Persoons, Dominique Schols, Steven De Jonghe and Ioannis K. Kostakis
Molecules 2024, 29(23), 5549; https://doi.org/10.3390/molecules29235549 - 25 Nov 2024
Viewed by 1140
Abstract
Thirteen new 4,7-disubstituted pyrimido[4,5-d]pyrimidines were synthesized via a straightforward methodology starting from thiourea. The anti-proliferative activity of these compounds was evaluated across a diverse panel of eight cancer cell lines, with derivatives 7d and 7h showing efficacy against several hematological cancer [...] Read more.
Thirteen new 4,7-disubstituted pyrimido[4,5-d]pyrimidines were synthesized via a straightforward methodology starting from thiourea. The anti-proliferative activity of these compounds was evaluated across a diverse panel of eight cancer cell lines, with derivatives 7d and 7h showing efficacy against several hematological cancer types. Furthermore, all compounds were assessed for their antiviral potency against a panel of viruses. Compounds featuring a cyclopropylamino group and an aminoindane moiety exhibited remarkable efficacy against human coronavirus 229E (HCoV-229E). These findings highlight the pyrimidino[4,5-d]pyrimidine scaffold as an interesting framework for the design of novel antiviral agents against HCoVs, with compounds 7a, 7b, and 7f emerging as strong candidates for further investigation. Full article
(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Heterocyclic Compounds)
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31 pages, 8543 KiB  
Article
N-Hydroxypiridinedione: A Privileged Heterocycle for Targeting the HBV RNase H
by Dimitrios Moianos, Maria Makri, Georgia-Myrto Prifti, Aristeidis Chiotellis, Alexandros Pappas, Molly E. Woodson, Razia Tajwar, John E. Tavis and Grigoris Zoidis
Molecules 2024, 29(12), 2942; https://doi.org/10.3390/molecules29122942 - 20 Jun 2024
Cited by 3 | Viewed by 2001
Abstract
Hepatitis B virus (HBV) remains a global health threat. Ribonuclease H (RNase H), part of the virus polymerase protein, cleaves the pgRNA template during viral genome replication. Inhibition of RNase H activity prevents (+) DNA strand synthesis and results in the accumulation of [...] Read more.
Hepatitis B virus (HBV) remains a global health threat. Ribonuclease H (RNase H), part of the virus polymerase protein, cleaves the pgRNA template during viral genome replication. Inhibition of RNase H activity prevents (+) DNA strand synthesis and results in the accumulation of non-functional genomes, terminating the viral replication cycle. RNase H, though promising, remains an under-explored drug target against HBV. We previously reported the identification of a series of N-hydroxypyridinedione (HPD) imines that effectively inhibit the HBV RNase H. In our effort to further explore the HPD scaffold, we designed, synthesized, and evaluated 18 novel HPD oximes, as well as 4 structurally related minoxidil derivatives and 2 barbituric acid counterparts. The new analogs were docked on the RNase H active site and all proved able to coordinate the two Mg2+ ions in the catalytic site. All of the new HPDs effectively inhibited the viral replication in cell assays exhibiting EC50 values in the low μM range (1.1–7.7 μM) with low cytotoxicity, resulting in selectivity indexes (SI) of up to 92, one of the highest reported to date among HBV RNase H inhibitors. Our findings expand the structure–activity relationships on the HPD scaffold, facilitating the development of even more potent anti-HBV agents. Full article
(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Heterocyclic Compounds)
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20 pages, 8390 KiB  
Article
Design, Synthesis and Evaluation of Antioxidant and NSAID Derivatives with Antioxidant, Anti-Inflammatory and Plasma Lipid Lowering Effects
by Panagiotis Theodosis-Nobelos, Gabriel Marc and Eleni A. Rekka
Molecules 2024, 29(5), 1016; https://doi.org/10.3390/molecules29051016 - 26 Feb 2024
Cited by 3 | Viewed by 1644
Abstract
Amides containing methyl esters of γ-aminobutyric acid (GABA), L-proline and L-tyrosine, and esters containing 3-(pyridin-3-yl)propan-1-ol were synthesized by conjugation with 3,5-di-tert-butyl-4-hydroxybenzoic, an NSAID (tolfenamic acid), or 3-phenylacrylic (cinnamic, (E)-3-(3,4-dimethoxyphenyl)acrylic and caffeic) acids. The rationale for the conjugation of such [...] Read more.
Amides containing methyl esters of γ-aminobutyric acid (GABA), L-proline and L-tyrosine, and esters containing 3-(pyridin-3-yl)propan-1-ol were synthesized by conjugation with 3,5-di-tert-butyl-4-hydroxybenzoic, an NSAID (tolfenamic acid), or 3-phenylacrylic (cinnamic, (E)-3-(3,4-dimethoxyphenyl)acrylic and caffeic) acids. The rationale for the conjugation of such moieties was based on the design of structures with two or more molecular characteristics. The novel compounds were tested for their antioxidant, anti-inflammatory and hypolipidemic properties. Several compounds were potent antioxidants, comparable to the well-known antioxidant, Trolox. In addition, the radical scavenging activity of compound 6 reached levels that were slightly better than that of Trolox. All the tested compounds demonstrated remarkable activity in the reduction in carrageenan-induced rat paw edema, up to 59% (compound 2, a dual antioxidant and anti-inflammatory molecule, with almost 2.5-times higher activity in this experiment than the parent NSAID). Additionally, the compounds caused a significant decrease in the plasma lipidemic indices in Triton-induced hyperlipidemic rats. Compound 2 decreased total cholesterol by 75.1% and compound 3 decreased triglycerides by 79.3% at 150 μmol/kg (i.p.). The hypocholesterolemic effect of the compounds was comparable to that of simvastatin, a well-known hypocholesterolemic drug. Additionally, all compounds lowered blood triglycerides. The synthesized compounds with multiple activities, as designed, may be useful as potential candidates for conditions involving inflammation, lipidemic deregulation and oxygen toxicity. Full article
(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Heterocyclic Compounds)
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16 pages, 2215 KiB  
Article
Synthesis and Biological Evaluation of 2-Substituted Quinazolin-4(3H)-Ones with Antiproliferative Activities
by Maria Karelou, Dionysis Kampasis, Amalia D. Kalampaliki, Leentje Persoons, Andreas Krämer, Dominique Schols, Stefan Knapp, Steven De Jonghe and Ioannis K. Kostakis
Molecules 2023, 28(23), 7912; https://doi.org/10.3390/molecules28237912 - 2 Dec 2023
Cited by 3 | Viewed by 2006
Abstract
Sixteen new 2-substituted quinazolines were synthesized using a straightforward methodology starting from 2-methoxybezoic acid or 3-methoxy-2-naphthoic acid. The anti-proliferative activity of the target compounds was evaluated against nine cancer cell lines. Additionally, all the compounds were screened for their potency and selectivity against [...] Read more.
Sixteen new 2-substituted quinazolines were synthesized using a straightforward methodology starting from 2-methoxybezoic acid or 3-methoxy-2-naphthoic acid. The anti-proliferative activity of the target compounds was evaluated against nine cancer cell lines. Additionally, all the compounds were screened for their potency and selectivity against a panel of 109 kinases and four bromodomains, using Differential Scanning Fluorimetry (DSF). Compound 17 bearing a 2-methoxyphenyl substitution along with a basic side chain displayed a remarkable profile against the majority of the tested cell lines. Full article
(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Heterocyclic Compounds)
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