3-PHENACYLURIDINE-DERIVED HYPNOTICS: ANTHOLOGY, STRUCTUREACTIVITY RELATIONSHIPS AND SYNTHESIS OF SEVERAL ACYCLONUCLEOSIDE ANALOGUES

This work was supported by the Russian Foundation for Basic Research, project # 18-33-00421

SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIPS OF THE NOVEL ISOTHIOBARBAMINE ANALOGUES WITH LOWERED BASICITY

This work was supported by the Russian Scientific Foundation, project № 19-13-00123

Diarylpyrimidine-Dihydrobenzyloxopyrimidine Hybrids: New, Wide-Spectrum Anti-HIV-1 Agents Active at (Sub)-Nanomolar Level.

Here, we describe a novel small series of nonnucleoside reverse transcriptase inhibitors (NNRTIs) that combine peculiar structural features of diarylpyrimidines (DAPYs) and dihydro-alkoxy-benzyl-oxopyrimidines (DABOs). These DAPYDABO hybrids (14) showed a characteristic SAR profile and a nanomolar anti-HIV-1 activity at both enzymatic and cellular level. In particular, the two compounds 4d and 2d, with a (sub)nanomolar activity against wild-type and clinically relevant HIV-1 mutant strains, were selected as lead compounds for next optimization studies

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

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

2-(Alkyl/aryl)amino-6-benzylpyrimidin-4(3H)-ones as inhibitors of wild-type and mutant HIV-1: enantioselectivity studies.

The single enantiomers of two pyrimidine-based HIV-1 non-nucleoside reverse transcriptase inhibitors, 1 (MC1501) and 2 (MC2082), were tested in both cellular and enzyme assays. In general, the R forms were more potent than their S counterparts and racemates and (R)-2 was more efficient than (R)-1 and the reference compounds, with some exceptions. Interestingly, (R)-2 displayed a faster binding to K103N RT with respect to WT RT, while (R)-1 showed the opposite behavior. © 2012 American Chemical Societ

Pyrimidine thioethers: A novel class of antidepressant agents, endowed with anxiolytic, performance enhancing and nootropic activity

A series of new pyrimidine thioethers, recognized as the key intermediates in the synthesis of S-DABO antivirals, were prepared and evaluated both in vivo and in silico. The purpose of this evaluation was to find novel structural analogues of the known antihypoxic drug Isothiobarbamine endowed with improved pharmacological profile. The in vivo studies led to the identification of compounds 5c, 5e, and 5f endowed with antidepressant/anxiolytic, performance enhancing, and nootropic properties. Compounds 5c and 5f were further tested in mice affected by social depression and were able to increase motor and tentative search activity compared to control groups, along with higher interaction frequency and better results in a sucrose preference test. Overall, these data suggested a better psychoemotional state of the animals, treated with compounds 5c, and 5f. Moreover, 5c and 5f exhibited minimal acute toxicity, lower than Fluoxetine hydrochloride. Molecular modelling studies finally indicated the plausible biomolecular mechanism of action of compounds 5c, 5e, and 5f, which seem to bind GABA-A, melatonin, and sigma-1 receptors. Moreover, three-dimensional structure-activity relationships enabled to define a SAR model that will be of great utility for the design of further structurally optimized compounds of the above mentioned chemotype