Rhodium(II) acetate-catalyzed stereoselective synthesis, SAR and anti-HIV activity of novel oxindoles bearing cyclopropane ring

• Published in: European journal of medicinal chemistry Vol. 46; no. 4; pp. 1181 - 1188
• Main Authors: Kumari, Garima, Nutan, Modi, Manoj, Gupta, Satish K., Singh, Ramendra K.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.04.2011; Elsevier
• Subjects: Acetates - chemistry; Anti-HIV; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Anti-HIV Agents - toxicity; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Catalysis; Cell Line; Cell Survival - drug effects; Chemistry, Medicinal; Cyclopropanes - chemical synthesis; Cyclopropanes - chemistry; Cyclopropanes - pharmacology; Cyclopropanes - toxicity; HIV-1 - drug effects; Indoles - chemistry; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Molecular Conformation; MTT assay; NNRTIs; Organometallic Compounds - chemistry; Oxindoles; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rhodium - chemistry; SAR; Science & Technology; Stereoisomerism; Stereoselective synthesis; Structure-Activity Relationship; Substrate Specificity; Oxindoles; Anti-HIV; SAR; MTT assay; Stereoselective synthesis; NNRTIs; DESIGN; COMPLEX; MECHANISM; SEARCH; CC-1065; BIOLOGICAL EVALUATIONS; ANTIVIRAL PROPERTIES; REVERSE-TRANSCRIPTASE INHIBITORS; LIGANDS; Cyclopropane derivatives; RNA-directed DNA polymerase; HIV-1 virus; Non nucleoside compound; Lactam; Stereoselectivity; Structure activity relation; Reverse transcriptase inhibitor; Antiviral; Chemical synthesis; Catalytic reaction; Enzyme; Transferases; Retroviridae; Enzyme inhibitor; Lentivirus; In vitro; Spiran; Virus; Nucleotidyltransferases; Human immunodeficiency virus; Indole derivatives
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.01.037

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. The insilico designing, stereoselective synthesis and in vitro assessment of anti-HIV activity of oxindole derivatives have been described. [Display omitted] ► Novel oxindoles as NNRTIs against HIV-1. ► Computer aided designing and stereoselective synthesis of oxindole derivatives. ► Mechanism of formation of cis and trans isomers and their separation using RP-HPLC. ► Assessment of in vitro anti-HIV activity and cytotoxicity using TZM-bl and CEM-GFP cell lines.