title: Synthesis, biological evaluation and molecular modeling of 4,6-diarylpyrimidines and diarylbenzenes as novel non-nucleosides HIV-1 reverse transcriptase inhibitors.
abstract: A series of novel 4,6-diarylpyrimidines (4,6-DAPY) and diarylbenzenes (DABE) compounds were synthesized and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Among them, the most potent HIV-1 inhibitors were 8b, 8d, 14b and 18 (EC(50) = 0.049, 0.381, 0.599 and 0.398 μM, respectively), with HIV-1 inhibitory activity improved or similar to nevirapine (NVP, EC(50) = 0.097 μM) and delavirdine (DEV, EC(50) = 0.55 μM). The other compounds displayed moderate activity (8c, EC(50) = 5.25 μM) or were inactive (8a and 14a) against HIV-1 replication. Molecular modeling studies were performed with the synthesized compounds in complex with the wild-type reverse transcriptase (RT). A correlation was found between the anti-HIV activity and the electrostatic energy of interaction with Lys101 residue. These findings enrich the SAR of these Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) families.
authors.affiliation: Departamento de Farmacia, Facultad de Ciencias Químicas, Ciudad Universitaria, Universidad Nacional de Córdoba, X5000HUA Córdoba, Argentina.
authors.forename: Sergio R
authors.initials: SR
authors.lastname: Ribone
authors.forename: Volker
authors.initials: V
authors.lastname: Leen
authors.forename: Marcela
authors.initials: M
authors.lastname: Madrid
authors.forename: Wim
authors.initials: W
authors.lastname: Dehaen
authors.forename: Dirk
authors.initials: D
authors.lastname: Daelemans
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.forename: Margarita C
authors.initials: MC
authors.lastname: Briñón
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D015498:HIV-2 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D006801:Humans; 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; D014407:Tumor Cells, Cultured
chemical_list: D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase