title: Molecular modeling, synthesis and biological evaluation of N-heteroaryl compounds as reverse transcriptase inhibitors against HIV-1.
abstract: Different N-heteroaryl compounds bearing pyrimidine and benzimidazole moieties have been designed in silico using Discovery studio 2.5 software, synthesized and evaluated for their inhibitory activity as reverse transcriptase inhibitors against HIV-1 replication using laboratory adapted strains HIV-1IIIB (X4, subtype B) and HIV-1Ada5 (R5, subtype B), and the primary isolates HIV-1UG070 (X4, subtype D) and HIV-1VB59 (R5, subtype C). Cell-based assay showed that compounds were active at 1.394 μm concentrations (Selectivity Index: 1.29-38.39). The studies on structure-activity relationship clearly suggested anti-HIV activity of pyrimidine and benzimidazole derivatives and these findings were consistent with the in vitro cell-based experimental data. The results of molecular modeling and docking confirmed that all compounds assumed a butterfly-like conformation and showed H-bond, 'π-π' and 'π-+' and hydrophobic interactions within flexible non-nucleoside inhibitor binding pocket of HIV-1 reverse transcriptase, similar to known non-nucleoside reverse transcriptase inhibitors, such as nevirapine. In view of the results obtained, it can be said that the chemical skeletons of N, N'-bis-(pyridin-2-yl)-succinamide (14 and 15) and 1, 4-bis-benzoimidazol-1-yl-butane-1, 4-dione (16 and 17) may be used for developing potent inhibitors of HIV-1 replication, with suitable structure/pharmacophore modifications.
authors: Nucleic Acids and Antiviral Research Laboratory, Department of Chemistry, University of Allahabad, Allahabad, 211002, India.
authors: Anuradha
authors: A
authors: Singh
authors: Dipti
authors: D
authors: Yadav
authors: Madhu
authors: M
authors: Yadav
authors: Ashwini
authors: A
authors: Dhamanage
authors: Smita
authors: S
authors: Kulkarni
authors: Ramendra K
authors: RK
authors: Singh
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D005838:Genotype; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics / Q000502:physiology; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D001562:Benzimidazoles; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C031000:benzimidazole; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; C030986:pyrimidine
keywords: HIV-1 reverse transcriptase; TZM-bl cell lines; anti-HIV activity; docking