Synthesis of Furoannelated Analogues of Emivirine (MKC‐442)

Abstract

Furoannelated analogues 1-alkoxymethyl-7-phenyl-5, 7-dihydro-1H-furo[3, 4-d]-pyrimidine-2, 4-diones of Emivirine (3a, b) were synthesized from the primary alcohols 1-alkoxymethyl-6-benzyl-5-hydroxymethyl-1H-pyrimidine-2, 4-dione (5a, b) using a radical ring closure reaction with Pb(OAc)(4). These analogues are conformationally restricted in order to fix the aromatic substituent of Emivirine in nearly the same position as it is in the case when the complex of Emivirine is bound to HIV-1 RT. However, the anti HIV-1 activities of 3a, b were considerably lower than those of the lead Emivirine.

Design, Synthesis, and Biological Evaluation of 1-[(2-Benzyloxyl/alkoxyl)methyl]-5-halo-6-aryluracils as Potent HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with an Improved Drug Resistance Profile

“…Halogenations at the C-5 position of 3 by reaction of PbO 2 with halogen in glacial acetic acid at room temperature led to 4a – 5b in high yield. Compounds 4a – 5b were silylated in situ with N , O -bis(trimethylsilyl)acetamide (BSA) and then N-1 alkylated with the appropriate alkyl chloromethyl ether, in the presence of LiI, to give 6a – 9b , in good yield, followed by reaction with aqueous dimethylamino solution to get 10a – 11b . , Finally, the uracil moiety was successfully converted to the 4-(1,2,4-triazolyl)pyrimidinone derivatives. Without purification, subsequent ammonia treatment yielded the target compounds 12a – 15b . − Structure assignments of these compounds were identified by NMR and mass spectral data.…”

Heterogeneous catalysts NiCoSe2 and NiCo2S4 for the effective synthesis of dihydropyrimidine-2-ones/thiones

“…Batzelladine-A 13 inhibits the binding of HIVgp-120-CDH, making it a potential candidate for HIV treatment. Emivirine J, 14 on the other hand, is specifically developed as an agent for the treatment of HIV (Fig. 1).…”

Flexibility vs rigidity of amphipathic peptide conjugates when interacting with lipid bilayers

“…The restriction of conformational mobility is one of the most general principles of drug design; there are numerous examples where rigidified molecules bind to biological targets more tightly and display higher efficacy and selectivity than their flexible analogs [24] . However, there are also many examples where this principle fails [25] , [26] , [27] , [28] , hence a deeper understanding of the role of conformational flexibility/rigidity in the interaction of drug candidates with their biological targets is of great value.…”