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Novel Dioxolan Derivatives of Indole as HIV‐1 Integrase Strand Transfer Inhibitors Active Against RAL Resistant Mutant Virus
Author(s) -
Singh Raja,
Yadav Pooja,
Tandon Vibha
Publication year - 2016
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.201601024
Subject(s) - integrase , mutant , raltegravir , indole test , chemistry , integrase inhibitor , virus , active site , human immunodeficiency virus (hiv) , wild type , stereochemistry , virology , biology , enzyme , biochemistry , gene , antiretroviral therapy , viral load
Abstract Drugs have been discovered to treat HIV‐1 but mutation in virus causing resistance to drug, necessitates a continuous development of novel molecules. We have developed new chemical constructs that target HIV‐1 integrase (HIV‐IN) and it's mutant. We have evaluated 22 dioxolan and malonyl derivatives of indole. It was observed that C‐3 substituted dioxolan derivatives 13 c and 13 o exhibited outstanding strand transfer inhibitory activity with IC 50 at 5.7 and 0.2 μM respectively. The therapeutic index of 13 o was comparable to raltegravir (RAL). Compounds 13 c and 13 o not only showed excellent antiviral activity (EC 50 ) in wild type, a moderate activity was also observed against mutant IN i. e. G140S (4.7 and 0.2 μM) and Y143R (5.0 and 0.37 μM) respectively. The computational study suggested that these inhibitors bind centrally at the active site of integrase making a close contact with the residues in or around the active site of wild type and mutant proteins. Thus the newly synthesized dioxolan derivatives opened the possibility for development of more effective IN inhibitors exploiting the strategy mentioned in our paper.