Synthesis and Biological Properties of Novel 2-Aminopyrimidin-4(3H)-ones Highly Potent against HIV-1 Mutant Strains

Abstract

Following the disclosure of dihydro-alkoxy-, dihydro-alkylthio-, and dihydro-alkylamino-benzyl-oxopyrimidines (DABOs, S-DABOs, and NH-DABOs) as potent and selective anti-HIV-1 agents belonging to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class, we report here the synthesis and biological evaluation of a novel series of DABOs bearing a N,N-disubstituted amino group or a cyclic amine at the pyrimidine-C2 position, a hydrogen atom or a small alkyl group at C5 and/or at the benzylic position, and the favorable 2,6-difluorobenzyl moiety at the C6 position (F2-N,N-DABOs). The new compounds were highly active up to the subnanomolar level against both wt HIV-1 and the Y181C mutant and at the submicromolar to nanomolar range against the K103N and Y188L mutant strains. Such derivatives were more potent than S-DABOs, NH-DABOs, and nevirapine and efavirenz were chosen as reference drugs. The higher inhibitor adaptability to the HIV-1 RT non-nucleoside binding site (NNBS) may account for the higher inhibitory effect exerted by the new molecules against the mutated RTs.

Substrate‐Induced Stable Enzyme–Inhibitor Complex Formation Allows Tight Binding of Novel 2‐Aminopyrimidin‐4(3H)‐ones to Drug‐Resistant HIV‐1 Reverse Transcriptase Mutants

“…The 2-Cl-6-F-N,N-DABOs were prepared following our reported procedures, [13,14] starting from 2-chloro-6-fluorophenylacetic or -phenylpropionic acid with a) N,N'-carbonyldiimidazole, b) potassium ethyl malonate or 2-methylmalonate in the presence of triethylamine and magnesium chloride, followed by acidic hydrolysis, and c) condensation of the obtained b-oxoesters with N,N-dimethylguanidine sulfate in the presence of sodium ethoxide (Scheme 1). Compounds MC1838 and MC1839, which share a chiral center at the benzylic position, were prepared and tested as racemates.…”

“…[13,14] We have previously shown that 2,6-F 2 -N,N-DABO derivatives owe their potent inhibitory activity to their very high affinity for the NNBS. [13] However, their kinetics showed low association rates to HIV-1 RT, behaving as slow-binding/high-affinity inhibitors.…”

Synthesis and Anti‐HIV‐1 Evaluation of Some Novel MC‐1220 Analogs as Non‐Nucleoside Reverse Transcriptase Inhibitors

“…1), which is used in racemic form [12][13][14][15][16]. The synthesis of MC-1220 and its analogs was previously published by Mai et al [12] and Bartolini et al [13] by condensation of the corresponding b-keto esters with guanidine sulfate derivatives. The b-keto esters, however, were prepared through multistep reactions [12].…”

“…The synthesis of MC-1220 and its analogs was previously published by Mai et al [12] and Bartolini et al [13] by condensation of the corresponding b-keto esters with guanidine sulfate derivatives. The b-keto esters, however, were prepared through multistep reactions [12]. Recently, Radi et al reported the synthesis of arylmethyl-functionalized S-DABOs and related analogs from C6-protected formyl pyrimidinone [17].…”

Synthesis and Biological Evaluation of 6‐Substituted 5‐Alkyl‐2‐(phenylaminocarbonylmethylthio)pyrimidin‐4(3H)‐ones as Potent HIV‐1 NNRTIs

“…[3][4][5] Among the NNRTIs, dihydroalkyloxybenzyloxopyrimidines (DABOs) were reported as potent HIV NNRTIs, with robust anti-HIV-1 activity against both the wild-type (wt) and a panel of clinically relevant HIV-1 mutants. [6] Three generations of DABO analogues have been found to date: dihydroalkyloxybenzyloxopyrimidines (O-DABOs), dihydroalkylthiobenzyloxopyrimidines (SDABOs), and dihydroalkylaminodifluorobenzyloxopyrimidines (N-DABOs), [7][8][9][10][11] from which many promising DABOs have been developed.…”