title: Rhodium(II) acetate-catalyzed stereoselective synthesis, SAR and anti-HIV activity of novel oxindoles bearing cyclopropane ring.
abstract: Novel oxindole derivatives bearing substituted cyclopropane ring have been designed on the basis of docking studies with HIV-1 RT using the software DS 2.5 and synthesized as probable NNRTIs against HIV-1 using rhodium(II) acetate-catalyzed stereoselective cyclopropanation reaction. The cyclopropane isomer, having trans relationship with respect to carbonyl of lactam moiety and functional group on the cyclopropane ring, was the major product in all cases along with a small amount of cis and methylene products. The trans isomers interacted well with HIV-1 RT through H-bonding with amino acids, like Lys101, Lys103, His235, Tyr318, constituting the non-nucleoside inhibitor binding pocket (NNIBP) during docking experiments. However, the compounds showed very little activity when subjected to in vitro anti-HIV-1 screening using β-galactosidase assay (TZM-bl cells) and GFP quantification (CEM-GFP cells). The very low level of in vitro HIV inhibition, in comparison to predicted EC(50) values on the basis of computational studies, during CEM-GFP screening using AZT as positive control indicated that probably the HIV RT is not the viral target and the molecules work through some different mechanism.
authors.affiliation: Nucleic Acids Research Laboratory, Department of Chemistry, University of Allahabad, Allahabad 211002, India.
authors.forename: Garima
authors.initials: G
authors.lastname: Kumari
authors.lastname: Nutan
authors.forename: Manoj
authors.initials: M
authors.lastname: Modi
authors.forename: Satish K
authors.initials: SK
authors.lastname: Gupta
authors.forename: Ramendra K
authors.initials: RK
authors.lastname: Singh
mesh_terms: D000085:Acetates / Q000737:chemistry*; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002384:Catalysis; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003521:Cyclopropanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D015497:HIV-1 / Q000187:drug effects*; D007211:Indoles / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D009942:Organometallic Compounds / Q000737:chemistry*; D000078183:Oxindoles; D012238:Rhodium / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000085:Acetates; D019380:Anti-HIV Agents; D003521:Cyclopropanes; D007211:Indoles; D009942:Organometallic Compounds; D000078183:Oxindoles; C022960:2-oxindole; C030797:cyclopropane; D012238:Rhodium