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Molecular Modeling, Synthesis, and Anti‐ HIV Activity of Novel Isoindolinedione Analogues as Potent Non‐nucleoside Reverse Transcriptase Inhibitors
Author(s) -
Kumari Garima,
Singh Ramendra K.
Publication year - 2016
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12620
Subject(s) - chemistry , sulfonamide , integrase , moiety , in vitro , reverse transcriptase , stereochemistry , amide , small molecule , thioamide , combinatorial chemistry , biochemistry , dna , rna , gene
Different isoindolinedione derivatives bearing imine, amide, thioamide, and sulfonamide linkages have been designed in silico using discovery studio software (BIOVIA, San Diego, CA, USA), synthesized, and evaluated for their anti‐ HIV activity. SAR studies revealed that the linkages in these molecules did affect their anti‐ HIV activity and the molecules having sulfonamide linkages were the most potent HIV ‐ RT inhibitors as the S=O bonds of the sulfonamide moiety interacted with Lys103 ( NH or carbonyl or both) and Pro236; the NH part of the sulfonamide linkage formed bond with carbonyl of Lys101. blood–brain barrier ( BBB ) plots were also studied, and it was found that all the designed molecules have potential to cross BBB , a very vital criteria for anti‐ HIV drugs. In vitro screening was performed using HIV ‐1 strain IIIB in MT ‐4 cells using the MTT assay, and it was seen that some of these molecules were effective inhibitors of HIV ‐1 replication at nanomolar concentration with selectivity indices ranging from 33.75 to 73.33 under in vitro conditions. Some of these molecules have shown good anti‐ HIV activity at 3–4 n m concentrations. These derivatives have potential to be developed as lead molecules effective against HIV ‐1. Novel isoindolinedione derivatives as probable NNRTI s have been synthesized and characterized. Some of these molecules have shown good anti‐ HIV activity at 3–4 n m concentrations.