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Uracil derivatives as HIV-1 capsid protein inhibitors: design, in silico, in vitro and cytotoxicity studies

A series of novel uracil derivatives such as bispyrimidine dione and tetrapyrimidine dione derivatives were designed based on the existing four-point pharmacophore model as effective HIV capsid protein inhibitors. The compounds were initially docked with an HIV capsid protein monomer to rationalize...

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Autores principales: Ramesh, Deepthi, Mohanty, Amaresh Kumar, De, Anirban, Vijayakumar, Balaji Gowrivel, Sethumadhavan, Aiswarya, Muthuvel, Suresh Kumar, Mani, Maheswaran, Kannan, Tharanikkarasu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9190787/
https://www.ncbi.nlm.nih.gov/pubmed/35765450
http://dx.doi.org/10.1039/d2ra02450k
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author Ramesh, Deepthi
Mohanty, Amaresh Kumar
De, Anirban
Vijayakumar, Balaji Gowrivel
Sethumadhavan, Aiswarya
Muthuvel, Suresh Kumar
Mani, Maheswaran
Kannan, Tharanikkarasu
author_facet Ramesh, Deepthi
Mohanty, Amaresh Kumar
De, Anirban
Vijayakumar, Balaji Gowrivel
Sethumadhavan, Aiswarya
Muthuvel, Suresh Kumar
Mani, Maheswaran
Kannan, Tharanikkarasu
author_sort Ramesh, Deepthi
collection PubMed
description A series of novel uracil derivatives such as bispyrimidine dione and tetrapyrimidine dione derivatives were designed based on the existing four-point pharmacophore model as effective HIV capsid protein inhibitors. The compounds were initially docked with an HIV capsid protein monomer to rationalize the ideas of design and to find the potential binding modes. The successful design and computational studies led to the synthesis of bispyrimidine dione and tetrapyrimidine dione derivatives from uracil and aromatic aldehydes in the presence of HCl using novel methodology. The in vitro evaluation in HIV p24 assay revealed five potential uracil derivatives with IC(50) values ranging from 191.5 μg ml(−1) to 62.5 μg ml(−1). The meta-chloro substituted uracil compound 9a showed promising activity with an IC(50) value of 62.5 μg ml(−1) which is well correlated with the computational studies. As expected, all the active compounds were noncytotoxic in BA/F3 and Mo7e cell lines highlighting the thoughtful design. The structure activity relationship indicates the position priority and lower log P values as the possible cause of inhibitory potential of the uracil compounds.
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spelling pubmed-91907872022-06-27 Uracil derivatives as HIV-1 capsid protein inhibitors: design, in silico, in vitro and cytotoxicity studies Ramesh, Deepthi Mohanty, Amaresh Kumar De, Anirban Vijayakumar, Balaji Gowrivel Sethumadhavan, Aiswarya Muthuvel, Suresh Kumar Mani, Maheswaran Kannan, Tharanikkarasu RSC Adv Chemistry A series of novel uracil derivatives such as bispyrimidine dione and tetrapyrimidine dione derivatives were designed based on the existing four-point pharmacophore model as effective HIV capsid protein inhibitors. The compounds were initially docked with an HIV capsid protein monomer to rationalize the ideas of design and to find the potential binding modes. The successful design and computational studies led to the synthesis of bispyrimidine dione and tetrapyrimidine dione derivatives from uracil and aromatic aldehydes in the presence of HCl using novel methodology. The in vitro evaluation in HIV p24 assay revealed five potential uracil derivatives with IC(50) values ranging from 191.5 μg ml(−1) to 62.5 μg ml(−1). The meta-chloro substituted uracil compound 9a showed promising activity with an IC(50) value of 62.5 μg ml(−1) which is well correlated with the computational studies. As expected, all the active compounds were noncytotoxic in BA/F3 and Mo7e cell lines highlighting the thoughtful design. The structure activity relationship indicates the position priority and lower log P values as the possible cause of inhibitory potential of the uracil compounds. The Royal Society of Chemistry 2022-06-13 /pmc/articles/PMC9190787/ /pubmed/35765450 http://dx.doi.org/10.1039/d2ra02450k Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Chemistry
Ramesh, Deepthi
Mohanty, Amaresh Kumar
De, Anirban
Vijayakumar, Balaji Gowrivel
Sethumadhavan, Aiswarya
Muthuvel, Suresh Kumar
Mani, Maheswaran
Kannan, Tharanikkarasu
Uracil derivatives as HIV-1 capsid protein inhibitors: design, in silico, in vitro and cytotoxicity studies
title Uracil derivatives as HIV-1 capsid protein inhibitors: design, in silico, in vitro and cytotoxicity studies
title_full Uracil derivatives as HIV-1 capsid protein inhibitors: design, in silico, in vitro and cytotoxicity studies
title_fullStr Uracil derivatives as HIV-1 capsid protein inhibitors: design, in silico, in vitro and cytotoxicity studies
title_full_unstemmed Uracil derivatives as HIV-1 capsid protein inhibitors: design, in silico, in vitro and cytotoxicity studies
title_short Uracil derivatives as HIV-1 capsid protein inhibitors: design, in silico, in vitro and cytotoxicity studies
title_sort uracil derivatives as hiv-1 capsid protein inhibitors: design, in silico, in vitro and cytotoxicity studies
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9190787/
https://www.ncbi.nlm.nih.gov/pubmed/35765450
http://dx.doi.org/10.1039/d2ra02450k
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