3,4-DIHYDRO-2-ALKOXY-6-BENZYL-4-OXOPYRIMIDINES (DABOS) - A NEW CLASS OF SPECIFIC INHIBITORS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1

A series of novel 3,4-dihydro-6-benzyl-4-oxopyrimidines substituted at both the C-5 and the C-2 positions were synthesized as potential anti -HIV agents. Preparation of the title compounds was achieved by conden sation of O-methylisourea with methyl 2-alkyl-4-phenylacetylacetate an d subsequent displacement of the methoxy group by reaction with a seri es of linear, ramified and cyclic alkoxy groups containing from three to six carbon units. Methyl 2-alkyl-4-phenylacetylacetates were prepar ed by alkylation of methyl 4-phenylacetylacetate, which was obtained s tarting from Meldrum's acid and phenacetyl chloride. Acid hydrolysis o f 3,4-dihydro-6-benzyl-2-methoxy-4-oxopyrimidines furnished the corres ponding 1,2,3,4-tetrahydro-6-benzyl-2,4-dioxopyrimidines. In acutely i nfected MT-4 cells, compounds 3e, 3o, 3q and 3r showed an anti-HIV-1 a ctivity as potent and/or selective as HEPT and ddl. Unlike HEPT, the r eplacement of a methyl for an hydrogen atom at position C-5 of 3,4-dih ydro-2-alkoxy-6-benzyl-4-oxopyrimidines (DABOs) did not abolish the an tiviral activity, as well as the substitution of the C-5 methyl for an ethyl group did not increase the potency. However, similarly to HEPT and its derivatives, DABOs targeted the HIV-1 reverse transcriptase an d neither inhibited the multiplication of HIV-2 in acutely infected MT -4 cells, nor that of HIV-1 in chronically infected H9/IIIB cells.