title: Molecular Modeling, Synthesis, and Anti-HIV Activity of Novel Isoindolinedione Analogues as Potent Non-nucleoside Reverse Transcriptase Inhibitors.
abstract: 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 nm concentrations. These derivatives have potential to be developed as lead molecules effective against HIV-1. Novel isoindolinedione derivatives as probable NNRTIs have been synthesized and characterized. Some of these molecules have shown good anti-HIV activity at 3-4 nm concentrations.
authors.affiliation: Nucleic Acids and Antiviral Research Laboratory, Department of Chemistry, University of Allahabad, Allahabad, India.
authors.forename: Garima
authors.initials: G
authors.lastname: Kumari
authors.affiliation: Nucleic Acids and Antiviral Research Laboratory, Department of Chemistry, University of Allahabad, Allahabad, India.
authors.forename: Ramendra K
authors.initials: RK
authors.lastname: Singh
mesh_terms: D001665:Binding Sites; D001812:Blood-Brain Barrier / Q000378:metabolism; D002460:Cell Line; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D054836:Indolizidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D054836:Indolizidines; D018894:Reverse Transcriptase Inhibitors; D013449:Sulfonamides; D054303:HIV Reverse Transcriptase
keywords: anti-HIV activity; blood-brain barrier; isoindolinediones; non-nucleoside reverse transcriptase inhibitors