Angela Rao

Discovery of 2,3-diaryl-1,3-thiazolidin-4-ones as potent anti-HIV-1 agents

Design, synthesis and anti-HIV activity of a series of 2,3-diaryl-1,3-thiazolidin-4-ones are reported. Some derivatives proved to be highly effective in inhibiting HIV-1 replication at nanomolar concentrations thereby acting as non-nucleoside HIV-1 RT inhibitors (NNRTIs). SAR studies evidenced that the nature of the substituents at the 2 and 3 positions of the thiazolidinone nucleus largely influenced the in vitro anti-HIV activity of this new class of potent antiviral agents.

Synthesis and anti-hIV activity of 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole structurally-related 1,2-substituted benzimidazoles.

The synthesis of 1,2-substituted benzimidazoles is reported. These novel derivatives share chemical similarities with 1-aryl-1H,3H-thiazolo[3,4-a]benzimidazoles, a class of HIV-1 NNRTIs studied widely. All compounds prepared were tested in MT-4 cells to explore their potential anti-HIV activity and were found to be less potent than 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole (TBZ).

Synthesis and anti-HIV activity of 2,3-diaryl-1,3-thiazolidin-4-(thi)one derivatives

Several 2,3-diaryl-1,3-thiazolidine-4-thione derivatives and 2,3-diaryl-1,3-thiazolidin-4-ones bearing a methyl group at C-5 position have been synthesized and tested as anti-HIV agents. The results of the in vitro tests showed that some of them proved to be effective inhibitors of HIV-1 replication.

Synthesis and anti-HIV activity of 2,3-diaryl-1,3-thiazolidin-4-ones

Several 1,3-thiazolidin-4-ones bearing a 2,6-dihalophenyl group at C-2 and a variously substituted phenyl ring at N-3 have been synthesized and tested as anti-HIV agents. The results of the in vitro tests showed that some of them proved to be effective inhibitors of HIV-1 replication.

Comparative molecular field analysis (CoMFA) and docking studies of non-nucleoside HIV-1 RT inhibitors (NNIs).

A set of TIBO derivatives endowed with reverse transcriptase (RT) inhibitory activity were analyzed by comparative molecular field analysis (CoMFA). Besides conventional steric and electrostatic fields, molecular lipophilicity potential (MLP) was also used as a third field in CoMFA. An informative and statistically significant model (q2 = 0.70, r2 = 0.90, s = 0.46) was obtained by taking into account the three field types together. The key molecular determinants governing the RT inhibition by TIBO congeners were detected at the 3-D level by a careful analysis of the CoMFA isocontour maps. To challenge the predictive ability of the CoMFA model, an external set of thiazolobenzimidazole (TBZ) derivatives were examined. Good predictions, suggesting a similar binding mode for TIBO and TBZ derivatives, emerged. Flexible docking experiments on TBZ, TIBO and other NNIs confirmed common binding characteristics, as found out also by CoMFA, and moreover a good correlation between calculated binding energies and inhibitory potency was found.

Anti-HIV agents: design and discovery of new potent RT inhibitors

This paper reports our work in the field of nonnucleoside RT inhibitors (NNRTIs). On the basis of extensive studies on 1H,3H-thiazolo[3,4-a]benzimidazole derivatives (TBZs) followed by structure-activity relationship (SAR) considerations and molecular modeling, the design and synthesis of a series of 2,3-diaryl-1,3-thiazolidin-4-ones have been performed. Some derivatives proved to be highly effective in inhibiting human immunodeficiency virus type-1 (HIV-1) replication at nanomolar concentrations with minimal toxicity, acting as reverse transcriptase (RT) inhibitors. Computational studies were used in order to probe the binding of our ligands to HIV-1-RT.

Efficient 3D database screening for novel HIV-1 IN inhibitors.

We describe the use of pharmacophore modeling as an efficient tool in the discovery of novel HIV-1 integrase (IN) inhibitors. A three-dimensional hypothetical model for the binding of diketo acid analogues to the enzyme was built by means of the Catalyst program. Using these models as a query for virtual screening, we found several compounds that contain the specified 3D patterns of chemical functions. Biological testing shows that our strategy was successful in searching for new structural leads as HIV-1 IN inhibitors.

Synthesis and biological activity of novel 1H,3H-thiazolo[3,4-a]benzimidazoles: non-nucleoside human immunodeficiency virus type 1 reverse transcriptase inhibitors.

Using a known human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase inhibitor (NNRTI), 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole (TBZ NSC 625487) as the lead structure for drug design, a series of novel 1H,3H-thiazolo[3,4-a]benzimidazole derivatives substituted on the benzene-fused ring was prepared. Their in vitro anti-HIV-1 activity, as well as their inhibitory effects on the viral reverse transcriptase, were evaluated. The structure-activity relationships for these compounds are described and the results suggest that the apolar binding pocket of RT, into which the NNRTIs must fit, can accommodate only groups with a limited size and shape.

Novel N1-substituted 1,3-dihydro-2H-benzimidazol-2-ones as potent non-nucleoside reverse transcriptase inhibitors.

Several N(1)-substituted 1,3-dihydro-2H-benzimidazol-2-ones were synthesized and evaluated as anti-HIV agents. Some of them proved to be highly effective in inhibiting HIV-1 replication at nanomolar concentration as potent non-nucleoside HIV-1 RT inhibitors (NNRTIs) with low cytotoxicity. SAR studies highlighted that the nature of the substituents at N(1) and on the benzene ring of benzimidazolone moiety significantly influenced the anti-HIV activity of this class of potent antiretroviral agents.

Synthesis and antitumour activity of 1h, 3h-thiazolo[3,4-a]benzimidazole derivatives

A series of 1H,3H‐thiazolo[3,4‐a]benzimidazoles were synthesized and tested for their in vitro antitumour activity against 60 human tumour cell lines. Some derivatives exhibited both tumour growth inhibition activity and cellular selectivity. In particular, compound 8c, the most active of the series, was very active towards all cell lines at concentrations ranging from 10−7 −10−5 M. Compound 4a, on the other hand, was highly selective against the CNS cancer cell line.