Assessment of the Antimicrobial and Antiproliferative Activities of Chloropyrazine-Tethered Pyrimidine Derivatives: In Vitro, Molecular Docking, and In-Silico Drug-Likeness Studies

Molecular hybridization (MH) of heterocyclic rings has enabled scientists to design and develop novel drugs and drug-like candidates. In our previous work, considering the importance of MH, we synthesized different kinds of chloropyrazine-tethered pyrimidine derivatives (<b>22</b>–<b&...

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Autores principales:	Richie R. Bhandare, Afzal Basha Shaik
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	molecular hybridization heterocyclic rings chloropyrazine pyrimidine antiproliferative activity antimicrobial activity Technology T Engineering (General). Civil engineering (General) TA1-2040 Biology (General) QH301-705.5 Physics QC1-999 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/fe0dd6beffe444b68eab5c30c39fe01a
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spelling	oai:doaj.org-article:fe0dd6beffe444b68eab5c30c39fe01a2021-11-25T16:36:54ZAssessment of the Antimicrobial and Antiproliferative Activities of Chloropyrazine-Tethered Pyrimidine Derivatives: In Vitro, Molecular Docking, and In-Silico Drug-Likeness Studies10.3390/app1122107342076-3417https://doaj.org/article/fe0dd6beffe444b68eab5c30c39fe01a2021-11-01T00:00:00Zhttps://www.mdpi.com/2076-3417/11/22/10734https://doaj.org/toc/2076-3417Molecular hybridization (MH) of heterocyclic rings has enabled scientists to design and develop novel drugs and drug-like candidates. In our previous work, considering the importance of MH, we synthesized different kinds of chloropyrazine-tethered pyrimidine derivatives (<b>22</b>–<b>40</b>) containing either substituted phenyl or heteroaryl rings at position-6 of the pyrimidine ring and evaluated their antitubercular activity. Herein, we report the antimicrobial and antiproliferative activities of <b>22</b>–<b>40</b>. The antiproliferative activity of the target hybrids was superior to the antimicrobial activity. However, some compounds showed greater antimicrobial activity than the standard drugs. For instance, among the nineteen derivatives, compound <b>31</b> containing a 2″,4″-dichlorophenyl ring, showed the most potent antibacterial and antifungal activities (MIC 45.37 µM), followed by compounds <b>25</b> and <b>30</b> bearing 4″-nitrophenyl and 2″,4″-difluorophenyl scaffolds with minimum inhibitory concentrations (MIC) values of 48.67 µM and 50.04 µM, respectively. Compound <b>35</b>, containing a bioisosteric 2″-pyridinyl ring, showed the most potent antiproliferative activity against the prostate cancer cell line (DU-145) with an IC<sub>50</sub> value of 5 ± 1 µg/mL. Additional testing of compounds <b>22</b>–<b>40</b> on human normal liver cells (LO2) indicated that the compounds were more selective to cancer cell lines over normal cells. Further, molecular docking of the most potent compound <b>35</b> against dihydrofolate reductase (DHFR) (PDB ID: 1U72) had a good binding affinity with a docking score of −6.834. The SwissADME program estimated the drug-likeness properties of compound <b>35</b>. Hybrid <b>35</b> is a potential lead molecule for the development of new anticancer drugs, whereas <b>31</b> is a promising antimicrobial lead candidate.Richie R. BhandareAfzal Basha ShaikMDPI AGarticlemolecular hybridizationheterocyclic ringschloropyrazinepyrimidineantiproliferative activityantimicrobial activityTechnologyTEngineering (General). Civil engineering (General)TA1-2040Biology (General)QH301-705.5PhysicsQC1-999ChemistryQD1-999ENApplied Sciences, Vol 11, Iss 10734, p 10734 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	molecular hybridization heterocyclic rings chloropyrazine pyrimidine antiproliferative activity antimicrobial activity Technology T Engineering (General). Civil engineering (General) TA1-2040 Biology (General) QH301-705.5 Physics QC1-999 Chemistry QD1-999
spellingShingle	molecular hybridization heterocyclic rings chloropyrazine pyrimidine antiproliferative activity antimicrobial activity Technology T Engineering (General). Civil engineering (General) TA1-2040 Biology (General) QH301-705.5 Physics QC1-999 Chemistry QD1-999 Richie R. Bhandare Afzal Basha Shaik Assessment of the Antimicrobial and Antiproliferative Activities of Chloropyrazine-Tethered Pyrimidine Derivatives: In Vitro, Molecular Docking, and In-Silico Drug-Likeness Studies
description	Molecular hybridization (MH) of heterocyclic rings has enabled scientists to design and develop novel drugs and drug-like candidates. In our previous work, considering the importance of MH, we synthesized different kinds of chloropyrazine-tethered pyrimidine derivatives (<b>22</b>–<b>40</b>) containing either substituted phenyl or heteroaryl rings at position-6 of the pyrimidine ring and evaluated their antitubercular activity. Herein, we report the antimicrobial and antiproliferative activities of <b>22</b>–<b>40</b>. The antiproliferative activity of the target hybrids was superior to the antimicrobial activity. However, some compounds showed greater antimicrobial activity than the standard drugs. For instance, among the nineteen derivatives, compound <b>31</b> containing a 2″,4″-dichlorophenyl ring, showed the most potent antibacterial and antifungal activities (MIC 45.37 µM), followed by compounds <b>25</b> and <b>30</b> bearing 4″-nitrophenyl and 2″,4″-difluorophenyl scaffolds with minimum inhibitory concentrations (MIC) values of 48.67 µM and 50.04 µM, respectively. Compound <b>35</b>, containing a bioisosteric 2″-pyridinyl ring, showed the most potent antiproliferative activity against the prostate cancer cell line (DU-145) with an IC<sub>50</sub> value of 5 ± 1 µg/mL. Additional testing of compounds <b>22</b>–<b>40</b> on human normal liver cells (LO2) indicated that the compounds were more selective to cancer cell lines over normal cells. Further, molecular docking of the most potent compound <b>35</b> against dihydrofolate reductase (DHFR) (PDB ID: 1U72) had a good binding affinity with a docking score of −6.834. The SwissADME program estimated the drug-likeness properties of compound <b>35</b>. Hybrid <b>35</b> is a potential lead molecule for the development of new anticancer drugs, whereas <b>31</b> is a promising antimicrobial lead candidate.
format	article
author	Richie R. Bhandare Afzal Basha Shaik
author_facet	Richie R. Bhandare Afzal Basha Shaik
author_sort	Richie R. Bhandare
title	Assessment of the Antimicrobial and Antiproliferative Activities of Chloropyrazine-Tethered Pyrimidine Derivatives: In Vitro, Molecular Docking, and In-Silico Drug-Likeness Studies
title_short	Assessment of the Antimicrobial and Antiproliferative Activities of Chloropyrazine-Tethered Pyrimidine Derivatives: In Vitro, Molecular Docking, and In-Silico Drug-Likeness Studies
title_full	Assessment of the Antimicrobial and Antiproliferative Activities of Chloropyrazine-Tethered Pyrimidine Derivatives: In Vitro, Molecular Docking, and In-Silico Drug-Likeness Studies
title_fullStr	Assessment of the Antimicrobial and Antiproliferative Activities of Chloropyrazine-Tethered Pyrimidine Derivatives: In Vitro, Molecular Docking, and In-Silico Drug-Likeness Studies
title_full_unstemmed	Assessment of the Antimicrobial and Antiproliferative Activities of Chloropyrazine-Tethered Pyrimidine Derivatives: In Vitro, Molecular Docking, and In-Silico Drug-Likeness Studies
title_sort	assessment of the antimicrobial and antiproliferative activities of chloropyrazine-tethered pyrimidine derivatives: in vitro, molecular docking, and in-silico drug-likeness studies
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/fe0dd6beffe444b68eab5c30c39fe01a
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Assessment of the Antimicrobial and Antiproliferative Activities of Chloropyrazine-Tethered Pyrimidine Derivatives: In Vitro, Molecular Docking, and In-Silico Drug-Likeness Studies

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