Triazole derivatives as non-nucleoside inhibitors of HIV-1 reverse transcriptase-Structure-activity relationships and crystallographic analysis

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 3, 2008, Pages 1131-1134

  Kirschberg, Thorsten A ^a   Balakrishnan, Mini ^a   Huang, Wei ^a   Hluhanich, Rebecca ^a   Kutty, Nilima ^a   Liclican, Albert C ^a   McColl, Damian J ^a   Squires, Neil H ^a   Lansdon, Eric B ^a  

^a GILEAD SCIENCES   (United States)

Author keywords

HIV 1 reverse transcriptase; NNRTI

Indexed keywords

DELAVIRDINE; EFAVIRENZ; GW 678248; NEVIRAPINE; RNA DIRECTED DNA POLYMERASE; RNA DIRECTED DNA POLYMERASE INHIBITOR; TRIAZOLE DERIVATIVE;

ANTIVIRAL ACTIVITY; ARTICLE; BINDING KINETICS; CONTROLLED STUDY; CRYSTALLOGRAPHY; DRUG BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN IMMUNODEFICIENCY VIRUS 1; MOLECULAR INTERACTION; NONHUMAN; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; STRUCTURE ACTIVITY RELATION; VIRUS INHIBITION; X RAY ANALYSIS;

ANTI-HIV AGENTS; COMBINATORIAL CHEMISTRY TECHNIQUES; CRYSTALLOGRAPHY, X-RAY; HIV REVERSE TRANSCRIPTASE; HIV-1; MOLECULAR CONFORMATION; MOLECULAR STRUCTURE; REVERSE TRANSCRIPTASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP; TRIAZOLES;

HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 38749122085     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.11.127     Document Type: Article

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24. 50) and cultured over a total of 35 days. Clonal sequencing of the terminal passage revealed the presence of V106I (21/25 clones, 84%) and F227L (15/25 clones, 60%). Consistent with the X-ray crystallographic structural data, K103N transcriptase was also present in a minority of clones (4/25, 16%). Viral pools from passage 7 (12.8 μM) and the terminal passage (51.2 μM) both demonstrated >75-fold resistance to 6 when compared to wild-type, and 4- and 10-fold reductions in susceptibility to nevirapine, respectively. No change in susceptibility to a control compound, the NRTI tenofovir, was observed for either viral pool.