Pyrimidine Thioethers:  A Novel Class of HIV-1 Reverse Transcriptase Inhibitors with Activity Against BHAP-Resistant HIV

Abstract

A series of pyrimidine thioethers was synthesized and evaluated for inhibitory properties against wild-type HIV-1 reverse transcriptase (RT) and an RT carrying the resistance-conferring mutation P236L. Modifications of both the pyrimidine and the functionality attached through the thioether yielded several analogues, which demonstrated activity against both enzyme types, with IC50 values as low as 190 nM against wild-type and 66 nM against P236L RT. Evaluation of a select number of pyrimidine thioethers in cell culture showed that these compounds have excellent activity against HIV-1IIIB-WT and retain good activity against a laboratory-derived HIV-1MF delavirdine-resistant variant.

Non-Nucleoside Reverse Transcriptase Inhibitors: The NNRTI Boom

“…Substitution of the sulphur with oxygen or nitrogen decreased or removed the activity. Oxidation of the sul- Nugent et al (1998). phur diminished the activity, and removal of the methylene linker resulted in compounds devoid of activity.…”

“…phur diminished the activity, and removal of the methylene linker resulted in compounds devoid of activity. Table 16 shows some of the compounds with activity against wildtype and the delavirdine-resistant HIV-1 (P236L) mutant (Nugent et al, 1998). Further study within the pyrimidine thioethers for compounds with broad activity against several NNRTI-resistant variants of HIV-1 have led to the furo[2,3-c]pyridinethiopyrimidine class of compounds.…”

Synthesis and Anti-HIV-1 and Anti-HCMV Activity of 1-Substituted 3-(3,5-Dimethylbenzyl)uracil Derivatives

“…8) Thereafter, many pyrimidine derivatives emerged as anti-HIV agents. 9,10) Against the background of these reports, we undertook a search for an anti-HIV agent by the structure-activity relationship (SAR) of the 1,3-disubstituted uracil 11) . It is demonstrated that the introduction of a cyanomethyl group onto N1 of uracil is effective for anti-HIV-1 activity.…”

Synthesis of 4-arylethyl-6-arylpyrimidine-2-thiols through aza-Michael addition/nucleophilic addition/aromatization tandem reactions

“…They are precursors to important organic compounds [3][4][5] and organometallic complexes [6][7][8]. In addition, they can also be utilized in the determination of many metal ions (Pb, Ru, Bi, Pd, Pt) as selective and sensitive ligands in analytical chemistry [9][10][11][12][13][14].…”