title: Molecular design, synthesis and biological evaluation of BP-O-DAPY and O-DAPY derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors.
abstract: This paper reports the synthesis and antiviral evaluation of a series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine the peculiar structural features of diarylpyrimidine derivatives (DAPYs) and benzophenone derivatives (BPs). The DAPY derivatives bearing benzoyl or alkoxyl substitutes on the A-ring showed the inhibitory activity against wild-type HIV-1 at the cellular level within the range of EC50 values from micromolar to nanomolar. Among these compounds, 1u exhibited the most potent anti-HIV-1 activity (EC50 = 0.06 ± 0.01 μM, SI > 6260), which were about 1.8-fold more active than nevirapine (NVP) and delavirdine (DLV). In addition, the binding modes with HIV-1 RT and the preliminary SAR studies of these derivatives were also considered for further investigation.
authors.affiliation: Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, People's Republic of China.
authors.forename: Shiqiong
authors.initials: S
authors.lastname: Yang
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.forename: Dirk
authors.initials: D
authors.lastname: Daelemans
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Ma
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Fen-Er
authors.initials: FE
authors.lastname: Chen
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001577:Benzophenones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D001577:Benzophenones; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C047723:benzophenone; D054303:HIV Reverse Transcriptase; C030986:pyrimidine
keywords: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide; 50% cell culture infectious dose; 50% cytotoxic concentration; 50% effective concentration; 50% inhibitory concentration; AZT; Antiviral activity; BPs; Benzophenone; CC(50); CCID(50); DAPYs; DLV; Diarylpyrimidine; EC(50); EFV; ESI; HIV-1; HIV-1 RT; Human immunodeficiency virus type 1 reverse transcriptase; IC(50); K(d); MTT; Molecular hybridization; NNIBP; NNRTIs; NVP; OD; SI; TMC125; TMC278; TMS; USFDA; United States Food and Drug Administration; benzophenone derivatives; delavirdine; diarylpyrimidine derivatives; dissociation constant; efavirenz; electrospray ionization; etravirine; nevirapine; non-nucleoside RT inhibitors; non-nucleoside inhibitor binding pocket; non-nucleoside reverse transcriptase inhibitors; optical density; rilpivirine; selectivity index; tetramethylsilane; wild-type; wt; zidovudine