Synthesis and Modeling Study of Some Potential Pyrimidine Derivatives as HIV Inhibitors

Abstract

A new series of 2-amino-6-((4-aryldiazenyl)benzyloxy)-4-chloropyrimidine derivatives 4 - 13 and 2,6-diamino-5-arylazo-4-chloro-pyrimidine analogs 15 - 20 were synthesized from the pyrimidine scaffolds 3 and 14, respectively, via diazotization with various amines. Nucleophilic displacement at the 2,4-diamino-5-arylazo-6-chloro-pyrimidine 16 by different amines afforded the 4-alkylamino analogs 21 - 27. All new compounds were evaluated for their in vitro anti-HIV activity in MT-4 cells as non-nucleoside reverse transcriptase inhibitors on the basis of our previous work. Screening results indicated that 10 and 11 were found to be the only compounds in the series inhibiting HIV-1 replication in cell cultures with EC50 of >1:23 and >2:92 μg mL-1 of a CC50 of 12.30 and 17.52 μg mL-1, resulting in a selectivity index of 10 and 6, respectively. In addition, preliminary structure-activity relationships and molecular modeling of these new analogs are detailed in this manuscript.

Synthesis, anti-HIV activity and molecular modeling study of some new pyrimidine analogues

“…Recently, reported the synthesis of azopyrimidine 5 [33], and selected here as a starting material for the synthesis of new azopyrimidine analogues having alkyl and aryl amino groups at C-4. Thus, compound 5 was subjected to a nucleophilic displacement of chlorine group by treatment with various amines in DMF at 90-100 °C for 4-5 h, leading to the new derivatives 6-13 in good to moderate yields (55-89 %), except the products 7 and 10 were obtained in a lower yields 32 and 36%, respectively (Scheme 1), might due to the steric factor (Scheme 1).…”