Reaction of 2-(nitroamino)pyrimidin-4(3H)-one derivatives with arylamines of low basicity in pivalic acid

Новаков, И. А.; Babushkin, A. S.; Brunilina, L. L.; Navrotskii, M. B.; Orlinson, B. S.; Robinovich, M. D.; Yablokov, A. S.

doi:10.1134/s1070428016110178

Cited by 2 publications

(3 citation statements)

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“…Starting conformations were modeled with the UCSF Chimera build module using as starting template the previous reported S -DABOs . UCSF Chimera version 1.11.2 was used to graphically inspect the molecular docking results obtained with Autodock Vina …”

Section: Methodsmentioning

confidence: 99%

“…The condensation of the β-oxoesters 15a – c , prepared as previously described, with thiourea in the presence of sodium ethoxide in dry ethanol under reflux conditions, provided the intermediates 6-((2,6-dihalophenyl)(methoxy)methyl)-5-methyl-2-thioxo-2,3-dihydropyrimidin-4(1 H )-ones 16a – c , which were then S -alkylated in dry DMF with the proper commercially available alkyl/cycloalkyl halide in the presence of anhydrous potassium carbonate to yield the final compounds 12a – i . The 6-((2,6-dihalophenyl)(methoxy)methyl)-5-methyl-2-(alkylamino)pyrimidin-4(3 H )-ones 13a – i and the 6-((2,6-dihalophenyl)(methoxy)methyl)-5-methyl-2-(methyl(propyl)amino)pyrimidin-4(3 H )-ones 14a – c were obtained from the 2-(nitroamino)pyrimidin-4-(3 H )-ones 17a – c , prepared by condensation of the β-oxoesters 15a – c with nitroguanidine in the presence of potassium ethoxide in dry ethanol under reflux conditions via aminolysis with the proper commercial amines in refluxing 1-butanol …”

Section: Introductionmentioning

confidence: 99%

“…The 6-((2,6-dihalophenyl)(methoxy)methyl)-5-methyl-2-(alkylamino)pyrimidin-4(3H)-ones 13a−i and the 6-((2,6-dihalophenyl)(methoxy)methyl)-5-methyl-2-(methyl(propyl)amino)pyrimidin-4(3H)-ones 14a−c were obtained from the 2-(nitroamino)pyrimidin-4-(3H)-ones 17a−c, prepared by condensation of the β-oxoesters 15a−c with nitroguanidine in the presence of potassium ethoxide in dry ethanol under reflux conditions 40 via aminolysis with the proper commercial amines in refluxing 1-butanol. 41 Elemental analyses and HPLC purity data for compounds 12−14 are reported in Tables S1 and S2, Supporting Information, respectively.…”

Section: ■ Introductionmentioning

confidence: 99%

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Effect of α-Methoxy Substitution on the Anti-HIV Activity of Dihydropyrimidin-4(3H)-ones

et al. 2018

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Conformational restriction applied to dihydrobenzylpyrimidin-4-(3H)-ones (DABOs) by the intoduction of a methyl group at the α-benzylic position is known to massively improve the anti-HIV-1 activity of these compounds. Here, we report the effects of methoxy substitution at the α-benzylic position in S-, NH-, and N,N-DABOs carrying 2,6-difluoro, 2-chloro-6-fluoro, or 2,6-dichloro substituted benzyl moieties. The various α-methoxy DABO series (12–14) present different SAR at the dihalo benzyl substitution, with the most potent compounds (12d,e and 13c) showing similar (picomolar/nanomolar) anti-HIV-1 potency as the corresponding α-methyl analogues against wt HIV-1, and 10–100-fold increased potency (up to low nanomolar) against clinically relevant K103N, Y181C, Y188L, IRLL98, and K103N+Y181C HIV-1 mutant strains, highlighting the importance of the α-methoxy substitution to provide highly efficient DABOs as “second generation” NNRTIs. HPLC enantioseparation of three of the most potent derivatives (12d, 13c, and 14c) provided single enantiomers with significant enantioselectivity in HIV-1 inhibition. Computational studies allowed to correlate the best antiviral activity with the (R) absolute configuration at the α-methoxy stereogenic center.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%