Pyrrolizine/Indolizine-NSAID Hybrids: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies

In the current study, eight new hybrids of the NSAIDs, ibuprofen and ketoprofen with five pyrrolizine/indolizine derivatives were designed and synthesized. The chemical structures of these hybrids were confirmed by spectral and elemental analyses. The antiproliferative activities of these hybrids (5...

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Autores principales:	Mohammed A. S. Abourehab, Alaa M. Alqahtani, Faisal A. Almalki, Dana M. Zaher, Ashraf N. Abdalla, Ahmed M. Gouda, Eman A. M. Beshr
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	pyrrolizine indolizine NSAIDs cytotoxicity cell cycle apoptosis Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/e3a501d1abb7432fba45b181cbc1b84d
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spelling	oai:doaj.org-article:e3a501d1abb7432fba45b181cbc1b84d2021-11-11T18:33:38ZPyrrolizine/Indolizine-NSAID Hybrids: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies10.3390/molecules262165821420-3049https://doaj.org/article/e3a501d1abb7432fba45b181cbc1b84d2021-10-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/21/6582https://doaj.org/toc/1420-3049In the current study, eight new hybrids of the NSAIDs, ibuprofen and ketoprofen with five pyrrolizine/indolizine derivatives were designed and synthesized. The chemical structures of these hybrids were confirmed by spectral and elemental analyses. The antiproliferative activities of these hybrids (5 μM) was investigated against MCF-7, A549, and HT-29 cancer cell lines using the cell viability assay, MTT assay. The results revealed 4–71% inhibition of the growth of the three cancer cell lines, where <b>8a</b>,<b>e</b>,<b>f</b> were the most active. In addition, an investigation of the antiproliferative activity of <b>8a</b>,<b>e</b>,<b>f</b> against MCF-7 cells revealed IC<sub>50</sub> values of 7.61, 1.07, and 3.16 μM, respectively. Cell cycle analysis of MCF-7 cells treated with the three hybrids at 5 μM revealed a pro-apoptotic increase in cells at preG1 and cell cycle arrest at the G1 and S phases. In addition, the three hybrids induced early apoptotic events in MCF-7 cells. The results of the molecular docking of the three hybrids into COX-1/2 revealed higher binding free energies than their parent compounds <b>5a</b>,<b>c</b> and the co-crystallized ligands, ibuprofen and SC-558. The results also indicated higher binding free energies toward COX-2 over COX-1. Moreover, analysis of the binding modes of <b>8a</b>,<b>e</b>,<b>f</b> into COX-2 revealed partial superposition with the co-crystallized ligand, SC-558 with the formation of essential hydrogen bonds, electrostatic, or hydrophobic interactions with the key amino acid His90 and Arg513. The new hybrids also showed drug-likeness scores in the range of 1.06–2.03 compared to ibuprofen (0.65) and ketoprofen (0.57). These results above indicated that compounds <b>8a</b>,<b>e</b>,<b>f</b> deserve additional investigation as potential anticancer candidates.Mohammed A. S. AbourehabAlaa M. AlqahtaniFaisal A. AlmalkiDana M. ZaherAshraf N. AbdallaAhmed M. GoudaEman A. M. BeshrMDPI AGarticlepyrrolizineindolizineNSAIDscytotoxicitycell cycleapoptosisOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6582, p 6582 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	pyrrolizine indolizine NSAIDs cytotoxicity cell cycle apoptosis Organic chemistry QD241-441
spellingShingle	pyrrolizine indolizine NSAIDs cytotoxicity cell cycle apoptosis Organic chemistry QD241-441 Mohammed A. S. Abourehab Alaa M. Alqahtani Faisal A. Almalki Dana M. Zaher Ashraf N. Abdalla Ahmed M. Gouda Eman A. M. Beshr Pyrrolizine/Indolizine-NSAID Hybrids: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies
description	In the current study, eight new hybrids of the NSAIDs, ibuprofen and ketoprofen with five pyrrolizine/indolizine derivatives were designed and synthesized. The chemical structures of these hybrids were confirmed by spectral and elemental analyses. The antiproliferative activities of these hybrids (5 μM) was investigated against MCF-7, A549, and HT-29 cancer cell lines using the cell viability assay, MTT assay. The results revealed 4–71% inhibition of the growth of the three cancer cell lines, where <b>8a</b>,<b>e</b>,<b>f</b> were the most active. In addition, an investigation of the antiproliferative activity of <b>8a</b>,<b>e</b>,<b>f</b> against MCF-7 cells revealed IC<sub>50</sub> values of 7.61, 1.07, and 3.16 μM, respectively. Cell cycle analysis of MCF-7 cells treated with the three hybrids at 5 μM revealed a pro-apoptotic increase in cells at preG1 and cell cycle arrest at the G1 and S phases. In addition, the three hybrids induced early apoptotic events in MCF-7 cells. The results of the molecular docking of the three hybrids into COX-1/2 revealed higher binding free energies than their parent compounds <b>5a</b>,<b>c</b> and the co-crystallized ligands, ibuprofen and SC-558. The results also indicated higher binding free energies toward COX-2 over COX-1. Moreover, analysis of the binding modes of <b>8a</b>,<b>e</b>,<b>f</b> into COX-2 revealed partial superposition with the co-crystallized ligand, SC-558 with the formation of essential hydrogen bonds, electrostatic, or hydrophobic interactions with the key amino acid His90 and Arg513. The new hybrids also showed drug-likeness scores in the range of 1.06–2.03 compared to ibuprofen (0.65) and ketoprofen (0.57). These results above indicated that compounds <b>8a</b>,<b>e</b>,<b>f</b> deserve additional investigation as potential anticancer candidates.
format	article
author	Mohammed A. S. Abourehab Alaa M. Alqahtani Faisal A. Almalki Dana M. Zaher Ashraf N. Abdalla Ahmed M. Gouda Eman A. M. Beshr
author_facet	Mohammed A. S. Abourehab Alaa M. Alqahtani Faisal A. Almalki Dana M. Zaher Ashraf N. Abdalla Ahmed M. Gouda Eman A. M. Beshr
author_sort	Mohammed A. S. Abourehab
title	Pyrrolizine/Indolizine-NSAID Hybrids: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies
title_short	Pyrrolizine/Indolizine-NSAID Hybrids: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies
title_full	Pyrrolizine/Indolizine-NSAID Hybrids: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies
title_fullStr	Pyrrolizine/Indolizine-NSAID Hybrids: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies
title_full_unstemmed	Pyrrolizine/Indolizine-NSAID Hybrids: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies
title_sort	pyrrolizine/indolizine-nsaid hybrids: design, synthesis, biological evaluation, and molecular docking studies
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/e3a501d1abb7432fba45b181cbc1b84d
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Pyrrolizine/Indolizine-NSAID Hybrids: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies

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