Elena S. Matyugina

Structure-activity evaluation of new uracil-based non-nucleoside inhibitors of HIV reverse transcriptase

A new series of potential nonnucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) based on the carbocyclic 5′-nor-uracil scaffold were designed and synthesized. Three different aspects of the scaffold were investigated: the effects of adding a linker between the carbocyclic and phenyl fragments, introduction of different substituents on the benzoyl residue and replacing the central carbocyclic ring with a benzyl group. Analogues of 2′,3′-dideoxy-2′,3′-didehydro-5′-nor-uridine, bearing 3,5-dichloro- or 3,5-dimethylbenzoyl groups, showed inhibitory activity against HIV-RT wild-type (IC50 5–10 μM) and mutants L100I (IC50 1.2–2.1 μM) and K103N (IC50 8–17 μM).

5′-Nor carbocyclic nucleosides: unusual nonnucleoside inhibitors of HIV-1 reverse transcriptase

A new series of potential nonnucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) based on the carbocyclic 5′-nor-uracil scaffold were designed and synthesized. Binding modes in the active site of the enzyme were studied computationally to provide insight on potential interactions. Several of the 2′,3′-dideoxy-2′,3′-didehydro-5′-nor-uridine analogues showed inhibitory activity against wild-type and mutant (L100I) HIV-RT with Ki 13–18 μM and 1–11 μM, respectively.

5′-Norcarbocyclic analogues of furano[2,3-d]pyrimidine nucleosides

Abstract 5′-Norcarbocyclic analogues of furano[2,3-d]pyrimidine nucleosides as well as 5-bromo and 5-iodouracil derivatives were synthesized to evaluate their potential antitumor activity. The halogenated derivatives display no cytotoxicity with respect to all tested cells: KB-3-1 (human epidermoid carcinoma), HeLa (human cervical epithelioid carcinoma), HuTu-80 (human duodenal cancer), B16 (mouse melanoma), and MDCK (normal epithelial). The cytotoxicity of the non-halogenated furano[2,3-d]pyrimidine derivatives increases with the lengthening of the alkyl chain of the substituent from 45 to 60 μm for octyl to from 3 to 10 μm for dodecyl.

5‐Arylaminouracil Derivatives: New Inhibitors of Mycobacterium tuberculosis

Three series of 5‐arylaminouracil derivatives, including 5‐(phenylamino)uracils, 1‐(4′‐hydroxy‐2′‐cyclopenten‐1′‐yl)‐5‐(phenylamino)uracils, and 1,3‐di‐(4′‐hydroxy‐2′‐cyclopenten‐1′‐yl)‐5‐(phenylamino)uracils, were synthesized and screened for potential antimicrobial activity. Most of compounds had a negative effect on the growth of the Mycobacterium tuberculosis H37Rv strain, with 100% inhibition observed at concentrations between 5 and 40 μg/mL. Of those, 1‐(4′‐hydroxy‐2′‐cyclopenten‐1′‐yl)‐3‐(4‴‐hydroxy‐2‴‐cyclopenten‐1‴‐yl)‐5‐(4″‐butyloxyphenylamino)uracil proved to be the most active among tested compounds against the M. tuberculosis multidrug‐resistant strain MS‐115 (MIC90 5 μg/mL). In addition, the thymidylate kinase of M. tuberculosis was evaluated as a possible enzymatic target.

Novel 5′-Norcarbocyclic Derivatives of Bicyclic Pyrrolo- and Furano[2,3-d]Pyrimidine Nucleosides

Here we report the synthesis and biological activity of new 5′-norcarbocyclic derivatives of bicyclic pyrrolo- and furano[2,3-d]pyrimidines with different substituents in the heterocyclic ring. Lead compound 3i, containing 6-pentylphenyl substituent, displays inhibitory activity with respect to a number of tumor cells with a moderate selectivity index value. Compound 3i induces cell death by the apoptosis pathway with the dissipation of mitochondrial potential.

Dual-targeted anti-TB/anti-HIV heterodimers

&NA; HIV and M. tuberculosis are two intersecting epidemics making the search for new dual action drugs against both pathogens extremely important. Here, we report on the synthesis and suppressive activities of five dual‐targeted HIV/TB compounds. These compounds are heterodimers of AZT, as anti‐HIV molecules, and 5‐substituted uracil derivatives, as anti‐TB molecules. We found that these compounds inhibit the growth of M. tuberculosis and suppress the replication of HIV in human cell cultures and human lymphoid tissues ex vivo. We identified one particular heterodimer that inhibited both HIV and the drug‐resistant TB strain MS‐115 most potently. This compound demonstrated low toxicity and had no cytostatic effect on cells in culture, constituting an ideal candidate for future development and further in vivo testing.