Design, synthesis, evaluation and thermodynamics of 1-substituted pyridylimidazo[1,5-a]pyridine derivatives as cysteine protease inhibitors.

Targeting papain family cysteine proteases is one of the novel strategies in the development of chemotherapy for a number of diseases. Novel cysteine protease inhibitors derived from 1-pyridylimidazo[1,5-a]pyridine representing pharmacologically important class of compounds are being reported here f...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Mohd Sajid Khan, Mohd Hassan Baig, Saheem Ahmad, Shapi Ahmad Siddiqui, Ashwini Kumar Srivastava, Kumar Venkatraman Srinivasan, Irfan A Ansari
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ec339d7965d944c58db256d573dc26df
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:ec339d7965d944c58db256d573dc26df
record_format	dspace
spelling	oai:doaj.org-article:ec339d7965d944c58db256d573dc26df2021-11-18T09:01:25ZDesign, synthesis, evaluation and thermodynamics of 1-substituted pyridylimidazo[1,5-a]pyridine derivatives as cysteine protease inhibitors.1932-620310.1371/journal.pone.0069982https://doaj.org/article/ec339d7965d944c58db256d573dc26df2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23940536/?tool=EBIhttps://doaj.org/toc/1932-6203Targeting papain family cysteine proteases is one of the novel strategies in the development of chemotherapy for a number of diseases. Novel cysteine protease inhibitors derived from 1-pyridylimidazo[1,5-a]pyridine representing pharmacologically important class of compounds are being reported here for the first time. The derivatives were initially designed and screened in silico by molecular docking studies against papain to explore the possible mode of action. The molecular interaction between the compounds and cysteine protease (papain) was found to be very similar to the interactions observed with the respective epoxide inhibitor (E-64c) of papain. Subsequently, compounds were synthesized to validate their efficacy in wet lab experiments. When characterized kinetically, these compounds show their Ki and IC50 values in the range of 13.75 to 99.30 µM and 13.40 to 96.50 µM, respectively. The thermodynamics studies suggest their binding with papain hydrophobically and entropically driven. These inhibitors also inhibit the growth of clinically important different types of Gram positive and Gram negative bacteria having MIC50 values in the range of 0.6-1.4 µg/ml. Based on Lipinski's rule of Five, we also propose these compounds as potent antibacterial prodrugs. The most active antibacterial compound was found to be 1-(2-pyridyl)-3-(2-hydroxyphenyl)imidazo[1,5-a]pyridine (3a).Mohd Sajid KhanMohd Hassan BaigSaheem AhmadShapi Ahmad SiddiquiAshwini Kumar SrivastavaKumar Venkatraman SrinivasanIrfan A AnsariPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 8, p e69982 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mohd Sajid Khan Mohd Hassan Baig Saheem Ahmad Shapi Ahmad Siddiqui Ashwini Kumar Srivastava Kumar Venkatraman Srinivasan Irfan A Ansari Design, synthesis, evaluation and thermodynamics of 1-substituted pyridylimidazo[1,5-a]pyridine derivatives as cysteine protease inhibitors.
description	Targeting papain family cysteine proteases is one of the novel strategies in the development of chemotherapy for a number of diseases. Novel cysteine protease inhibitors derived from 1-pyridylimidazo[1,5-a]pyridine representing pharmacologically important class of compounds are being reported here for the first time. The derivatives were initially designed and screened in silico by molecular docking studies against papain to explore the possible mode of action. The molecular interaction between the compounds and cysteine protease (papain) was found to be very similar to the interactions observed with the respective epoxide inhibitor (E-64c) of papain. Subsequently, compounds were synthesized to validate their efficacy in wet lab experiments. When characterized kinetically, these compounds show their Ki and IC50 values in the range of 13.75 to 99.30 µM and 13.40 to 96.50 µM, respectively. The thermodynamics studies suggest their binding with papain hydrophobically and entropically driven. These inhibitors also inhibit the growth of clinically important different types of Gram positive and Gram negative bacteria having MIC50 values in the range of 0.6-1.4 µg/ml. Based on Lipinski's rule of Five, we also propose these compounds as potent antibacterial prodrugs. The most active antibacterial compound was found to be 1-(2-pyridyl)-3-(2-hydroxyphenyl)imidazo[1,5-a]pyridine (3a).
format	article
author	Mohd Sajid Khan Mohd Hassan Baig Saheem Ahmad Shapi Ahmad Siddiqui Ashwini Kumar Srivastava Kumar Venkatraman Srinivasan Irfan A Ansari
author_facet	Mohd Sajid Khan Mohd Hassan Baig Saheem Ahmad Shapi Ahmad Siddiqui Ashwini Kumar Srivastava Kumar Venkatraman Srinivasan Irfan A Ansari
author_sort	Mohd Sajid Khan
title	Design, synthesis, evaluation and thermodynamics of 1-substituted pyridylimidazo[1,5-a]pyridine derivatives as cysteine protease inhibitors.
title_short	Design, synthesis, evaluation and thermodynamics of 1-substituted pyridylimidazo[1,5-a]pyridine derivatives as cysteine protease inhibitors.
title_full	Design, synthesis, evaluation and thermodynamics of 1-substituted pyridylimidazo[1,5-a]pyridine derivatives as cysteine protease inhibitors.
title_fullStr	Design, synthesis, evaluation and thermodynamics of 1-substituted pyridylimidazo[1,5-a]pyridine derivatives as cysteine protease inhibitors.
title_full_unstemmed	Design, synthesis, evaluation and thermodynamics of 1-substituted pyridylimidazo[1,5-a]pyridine derivatives as cysteine protease inhibitors.
title_sort	design, synthesis, evaluation and thermodynamics of 1-substituted pyridylimidazo[1,5-a]pyridine derivatives as cysteine protease inhibitors.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/ec339d7965d944c58db256d573dc26df
work_keys_str_mv	AT mohdsajidkhan designsynthesisevaluationandthermodynamicsof1substitutedpyridylimidazo15apyridinederivativesascysteineproteaseinhibitors AT mohdhassanbaig designsynthesisevaluationandthermodynamicsof1substitutedpyridylimidazo15apyridinederivativesascysteineproteaseinhibitors AT saheemahmad designsynthesisevaluationandthermodynamicsof1substitutedpyridylimidazo15apyridinederivativesascysteineproteaseinhibitors AT shapiahmadsiddiqui designsynthesisevaluationandthermodynamicsof1substitutedpyridylimidazo15apyridinederivativesascysteineproteaseinhibitors AT ashwinikumarsrivastava designsynthesisevaluationandthermodynamicsof1substitutedpyridylimidazo15apyridinederivativesascysteineproteaseinhibitors AT kumarvenkatramansrinivasan designsynthesisevaluationandthermodynamicsof1substitutedpyridylimidazo15apyridinederivativesascysteineproteaseinhibitors AT irfanaansari designsynthesisevaluationandthermodynamicsof1substitutedpyridylimidazo15apyridinederivativesascysteineproteaseinhibitors
_version_	1718421058254536704

Design, synthesis, evaluation and thermodynamics of 1-substituted pyridylimidazo[1,5-a]pyridine derivatives as cysteine protease inhibitors.

Ejemplares similares