Novel 1,2,3-thiadiazole derivatives as HIV-1 NNRTIs with improved potency: Synthesis and preliminary SAR studies

• Published in: Bioorganic & medicinal chemistry 2009-08, Vol.17 (16), p.5920-5927
• Main Authors: Zhan, Peng, Liu, Xinyong, Li, Zhenyu, Fang, Zengjun, Li, Zhong, Wang, Defeng, Pannecouque, Christophe, Clercq, Erik De
• Format: Article
• Language: English
• Subjects: Acetamides - chemical synthesis; Acetamides - chemistry; Acetamides - pharmacology; Acquired Immunodeficiency Syndrome - drug therapy; AIDS; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral activity; Antiviral agents; Binding Sites; Biological and medical sciences; Cell Line; Computer Simulation; Heterocycle; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - metabolism; HIV-1; HIV-1 - drug effects; Humans; Medical sciences; NNRTIs; Pharmacology. Drug treatments; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Structure-Activity Relationship; Thiadiazole thioacetanilides; Thiadiazoles - chemical synthesis; Thiadiazoles - chemistry; Thiadiazoles - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.07.004

The compound 7c was built and docked into the NNRTIs binding pocket (NNIBP) of HIV-1 RT (PDB code: 3DLG) using Autodock Vina [ http://vina.scripps.edu]. The docking result of 7c is showed by PyMOL. A novel synthetic route and anti-HIV activity evaluation of a new series of 2-(4-(2,4-dibromophenyl)-1,2,3-thiadiazol-5-ylthio)acetamide (TTA) derivatives are described. Bioactivity assay indicated that most of the title compounds showed good activities against HIV-1. In particular, compound 7c displayed the most potent anti-HIV-1 activity (EC 50 = 36.4 nM), inhibiting HIV-1 replication in MT-4 cells more effectively than NVP (by sevenfold) and DLV (by eightfold). The preliminary structure–activity relationships (SAR) of the newly synthesized congeners are discussed, and molecular modeling of compound 7c in complex with HIV-1 RT is described, allowing rationalization of some SAR conclusions.