Synthesis of a Series of 4-(Arylethynyl)-6-chloro-4-cyclopropyl-3,4-dihydroquinazolin-2(1H)-ones as Novel Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors

Abstract

As part of an ongoing effort to prepare novel non-nucleoside inhibitors of human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT), a series of 4-(arylethynyl)-6-chloro-4-cyclopropyl-3,4-dihydroquinazolin -2(1H)-ones 4aa-l has been prepared. Target compounds 4a-e were synthesized via addition of various 1-lithio-2-(aryl)alkyne nucleophiles to a 1-protected-4-cyclopropylquinazolin-2(1H)-one (7), followed by deprotection. The 3-methyl compound 4aa was prepared in an analogous manner, with the 3-alkylation performed prior to deprotection. Alternatively, the target compounds 4f-l were prepared by addition of 1-lithio-2-(trimethylsilyl)acetylene to 7, followed by deprotection and subsequent palladium-catalyzed coupling with various aryl halides. By incorporating an aryl group onto the end of the 4-acetylene functionality, the requirement for a metabolically labile 3-methyl group on the dihydroquinazolinone nucleus has been eliminated. A number of the target compounds were shown to be potent inhibitors of HIV-1 RT. Compound 4a, which had exhibited the most favorable overall biological profile, was resolved via a four-step procedure to provide the enantiomers 13a and 13b. Compound 13a having the (-)-4(S) configuration was shown to be the active enantiomer and was selected as a candidate for further investigation.

Facile preparation of 3-substituted 2-quinazolinones via electrogenerated base

“…Merck 11 was interested in the synthesis of a series of 4-(arylethynyl)-6-chloro-4-cyclopropyl-3,4-dihydroquinazolin-2 (1H)-ones as novel non-nucleoside HIV-1 reverse-transcriptase inhibitors. Modification at the 3-and 4-positions of the quinazolinone ring by different substituents afforded potent and selective T-type calcium channel antagonist 12,13 that displayed in vivo central nervous system efficacy in epilepsy and tremor models.…”

L-743, 726 (DMP-266): a novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase

“…The discovery of the benzoxazin-2-one NNRTIs is an outgrowth of our previous work on the 3,4-dihydroquinazolin-2(1H)-one-based RT inhibitors (19). The leading member of this class, L-743,726 (DMP-266), was found to be a potent inhibitor of wild-type HIV-1 in cell culture.…”

Synthetic Strategies for the Construction of δ-Carbolines: A Chemical Ladder in Search of Novel Drugs

“…Likewise, L-608,788 (Fig. (8c)) became the lead molecule in another class of dihydroquinazolinethione derivatives and optimisation on this molecule led to a very potent once daily dosing molecule Efavirenz [105]. Fig.…”