title: Diaryltriazine non-nucleoside reverse transcriptase inhibitors are potent candidates for pre-exposure prophylaxis in the prevention of sexual HIV transmission.
abstract: OBJECTIVE
  Pre-exposure prophylaxis and topical microbicides are important strategies in the prevention of sexual HIV transmission, especially since partial protection has been shown in proof-of-concept studies. In search of new candidate drugs with an improved toxicity profile and with activity against common non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV, we have synthesized and investigated a library of 60 new diaryltriazine analogues.
  
  
  METHODS
  From this library, 15 compounds were evaluated in depth using a broad armamentarium of in vitro assays that are part of a preclinical testing algorithm for microbicide development. Antiviral activity was assessed in a cell line, and in primary human cells, against both subtype B and subtype C HIV-1 and against viruses resistant to therapeutic NNRTIs and the candidate NNRTI microbicide dapivirine. Toxicity towards primary blood-derived cells, cell lines originating from the female reproductive tract and female genital microflora was also studied.
  
  
  CONCLUSIONS
  We identified several compounds with highly potent antiviral activity and toxicity profiles that are superior to that of dapivirine. In particular, compound UAMC01398 is an interesting new candidate that warrants further investigation because of its superior toxicity profile and potent activity against dapivirine-resistant viruses.
authors: Department of Biomedical Sciences, Institute of Tropical Medicine, B-2000 Antwerp, Belgium. karien@itg.be
authors: Kevin K
authors: KK
authors: Ariën
authors: Muthusamy
authors: M
authors: Venkatraj
authors: Johan
authors: J
authors: Michiels
authors: Jurgen
authors: J
authors: Joossens
authors: Katleen
authors: K
authors: Vereecken
authors: Pieter
authors: P
authors: Van der Veken
authors: Saïd
authors: S
authors: Abdellati
authors: Vicky
authors: V
authors: Cuylaerts
authors: Tania
authors: T
authors: Crucitti
authors: Leo
authors: L
authors: Heyndrickx
authors: Jan
authors: J
authors: Heeres
authors: Koen
authors: K
authors: Augustyns
authors: Paul J
authors: PJ
authors: Lewi
authors: Guido
authors: G
authors: Vanham
mesh_terms: D000818:Animals; D000891:Anti-Infective Agents, Local / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018890:Chemoprevention / Q000379:methods; D004353:Drug Evaluation, Preclinical; D005260:Female; D015658:HIV Infections / Q000517:prevention & control / Q000635:transmission; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D018894:Reverse Transcriptase Inhibitors / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D014227:Triazines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000891:Anti-Infective Agents, Local; D018894:Reverse Transcriptase Inhibitors; D014227:Triazines
keywords: NNRTIs; cytotoxicity; lactobacilli; microbicides; triazines