Dihydro(alkylthio)(naphthylmethyl)oxopyrimidines:  Novel Non-Nucleoside Reverse Transcriptase Inhibitors of the S-DABO Series

Abstract

Novel compounds related to 2-(cyclohexylthio)-3,4-dihydro-5-methyl-6-(3-methylbenzyl)-4-ox opyrimidine (3c, MC 639) have been synthesized and tested as inhibitors of human immunodeficiency virus type-1 (HIV-1). Reaction of thiourea with ethyl arylmethylacetoacetates furnished 5-alkyl-6-(arylmethyl)-3,4-dihydro-2-mercapto-4-oxopyrimidines which were then alkylated at the sulfur atom to afford the required 2-alkylthio or 2-cycloalkylthio derivatives (S-DABOs). Chemical modifications at N-3, C-4, and C-6 of the pyrimidine ring were attempted with the aim of improving antiretroviral activity. In particular, replacement of the benzyl group with the 1-naphthylmethyl moiety enhanced the activity of S-DABOs, whereas N-3 alkylation and C=O transformation into C=S at position 4 of the pyrimidine ring led to compounds devoid of anti-HIV-1 activity. Lower activity was generally observed when 1-naphthylmethyl was replaced by the isomeric 2-naphthylmethyl moiety. The most active compounds showed activity in the low micromolar range with EC50 values comparable to that of nevirapine.

Synthesis and anti‐HIV activity of HEPT and S‐DABO‐analogues with 5‐Benzyl and 5‐Phenyl substituents

“…In this investigation, 5-phenyl and 5-benzyl groups are used as examples of aromatic substituents and when they are compared with the 5-isopropyl group in MKC-442, they also represent more bulky substituents. 5,6-Dibenzyl-2-thiouracil is also S-alkylated to give new S-DABO (dihydroalkoxybenzyloxopyrimidine) analogues of compounds that have shown remarkably high activity against HIV-1 [4].…”

Chiral resolution and molecular modeling investigation ofrac-2-cyclopentylthio-6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-5-methylpyrimidin-4(3H)-one (MC-1047), a potent anti-HIV-1 reverse transcriptase agent of the DABO class

“…Replacement of phenylmethyl with the bulkier 1-naphthylmethyl moiety gave DATNOs, 6 a potent subfamily of DABOs. Further improvement of antiviral potency was obtained by introducing at the C-6 position a 2,6-difluorophenylmethyl chain (difluorothioDABOs, F 2 -S-DABOs).…”

Synthesis of imidazoles as novel emivirine and S‐DABO analogues

“…The dihydroalkoxybenzyloxopyrimidines (DABO) and their thio analogues (S-DABO) [5][6][7] are closely related to the HEPT derivatives. 6-Benzyl-4-oxopyrimidines were synthesized as dihydrofolate reductase inhibitors and because of their structural similarities with HEPT, they were also tested against HIV and some were found active.…”