Yenamandra S. Prabhakar

Topological descriptors in modeling the HIV inhibitory activity of 2-aryl-3-pyridyl-thiazolidin-4-ones.

The HIV-1 RT inhibitory activity of 2-(2,6-dihalophenyl)-3-(substituted pyridin-2-yl)-thiazolidin-4-ones has been analyzed with different topological descriptors obtained from DRAGON software. Here, simple topological descriptors (TOPO), Galvez topological charge indices (GVZ) and 2D autocorrelation descriptors (2DAUTO) have been found to yield good predictive models for the activity of these compounds. The correlations obtained from the TOPO class descriptors suggest that less extended or compact saturated structural templates would be better for the activity. The participating GVZ class descriptors suggest that they have same degree of influence on the activity. In 2DAUTO class, the large participation of descriptors of lags seven and three indicate the association of activity information with the seven and three centered structural fragments of these compounds. The physicochemical weighting components of these descriptors suggest homogeneous influence of mass, volume, electronegativity and/ or polarizability on the activity.

CoMFA and CoMSIA studies on thiazolidin-4-one as anti-HIV-1 agents

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on thiazolidin-4-one class of compounds as HIV-1 reverse transcriptase (HIV-1 RT) inhibitors using global minima and crystal structure conformations. Results obtained from the crystal structure-based model yielded superior statistical data (r(cv)(2) values of 0.683 for CoMFA and 0.678 for CoMSIA) when compared to those obtained by the global minima-based model (r(cv)(2) values of 0.625 and 0.654 for CoMFA and CoMSIA, respectively). The models were validated using an external test set of 47 compounds. The predictive r(2) values for the crystal-based CoMFA and CoMSIA models were 0.735 and 0.739, respectively, while the corresponding predictive r(2) values for the global minima-based CoMFA and CoMSIA models were 0.654 and 0.635, respectively. 3D contour maps generated from these models provide the regions in space where interactive fields may influence the activity. The superimposition of contour maps on the active site of HIV-1 reverse transcriptase additionally helped in understanding the structural requirements of these inhibitors. The results provide insight for predictive and diagnostic aspects of this class of HIV-1 RT inhibitors for better activity.

Synthesis and QSAR Studies on Thiazolidinones as Anti-HIV Agents

Selected 4-thiazolidinone have been synthesized and tested as anti-HIV activity. The results of the in vitro tests showed that one of the compounds, 5, inhibited the enzyme at 0.204 microM concentration with minimal toxicity to MT-4 cell. Furthermore, the QSAR studies indicated the role of PMIZ, Ovality and Total energy content of the compounds in rationalizing the activity.

Cypermethrin Induces Astrocyte Apoptosis by the Disruption of the Autocrine/Paracrine Mode of Epidermal Growth Factor Receptor Signaling

Cypermethrin is reported to affect astrocytes in rat brain; however, its mechanism of action is obscure. Here, we observed an increase in apoptosis in the cortical astrocytes upon treatment of rats with cypermethrin. We then characterized the mechanism governing the apoptosis. Because the epidermal growth factor receptor (EGFR) signaling regulates the survival of astrocytes, we investigated the effect of cypermethrin on EGFR activation. The astrocytes exhibited an early and irreversible attenuation in the basal EGFR phosphorylation. Supportively, molecular docking studies revealed considerable homology in the docking mode of cypermethrin and the known EGFR inhibitors, erlotinib and AG1478, to the kinase domain of EGFR. Furthermore, treatment with cypermethrin demonstrated a downregulation in the intracellular and secreted levels of heparin-binding epidermal growth factor (HB-EGF), an EGFR ligand. AG1478 reduced the synthesis of HB-EGF, suggesting the dependence of HB-EGF on EGFR activation. In addition, a neutralizing antibody against HB-EGF diminished the basal EGFR levels, indicating ligand-dependent expression of EGFR. Likewise, cypermethrin caused irreversible suppression in the basal EGFR levels, which induced apoptosis in astrocytes. The apoptosis was prevented by exogenous HB-EGF. These data imply an autocrine/paracrine mode of action of HB-EGF-EGFR in astrocyte survival. Consequently, cypermethrin induced a mitochondria-mediated apoptosis, characterized by rise in Bax/Bcl-2 ratio and cleavage of caspase-9, -3, and -7, and the effect was prevented by HB-EGF. HB-EGF activated the extracellular signal-regulated kinases and AKT pathways that protected against apoptosis. Together, these data demonstrate that cypermethrin induces astrocyte apoptosis by disrupting the autocrine/paracrine mode of HB-EGF-EGFR signaling at two levels, irreversible loss of basal EGFR and downregulation of HB-EGF.

Juglone derivatives as antitubercular agents: A rationale for the activity profile

The antitubercular activity and cytotoxicity of juglone derivatives were analyzed with the topological and molecular surface features from a web-based server, MODEL (MOlecular DEscriptor Lab). Analysis of the structural features in conjunction with the biological endpoints in Combinatorial Protocol in Multiple Linear Regression led to the identification of seven descriptors for modeling the activity and six descriptors for that of the toxicity of the compounds. Analysis of these descriptors in PLS highlighted their relative significance in modulating the biological response. They suggested that structures with compact molecular arrangement, partial positive surface areas and increased autocorrelation with small lag values may lead to better antitubercular activity.

QSAR study on tetrahydroquinoline analogues as plasmodium protein farnesyltransferase inhibitors: A comparison of rationales of malarial and mammalian enzyme inhibitory activities for selectivity

The quantitative structure-activity relationships of Plasmodium falciparum and Rat protein farnesyltransferase (PFT) inhibitory activities of 6-cyano-1-(3-methyl-3H-imidazoly-4-ylmethyl)-3-substituted-1,2,3,4-tetrahydroquinoline (THQ) analogues are investigated in order to explore the similarities/deviations between the two enzymes for these analogues. The structure space of a ligand (BMS-214662) bound to Rat-PFT (PDB code 1SA5) has been used as the conformational space of the compounds under investigation. The study has been carried out using the combinatorial protocol in multiple linear regression with several 2D- and 3D-descriptors from molecular operating environment (MOE) representing the physicochemical and electronic features of the compounds. The molecular potential energy and partially charged van der Waals surface areas have taken part in the PFT models. They suggested in favor of molecular arrangement with minimum energy and low positively/negatively charged surfaces for optimum Pf-PFT inhibitory activity. Furthermore, less hydrophobic compounds are preferred for the activity. The Rat-PFT inhibitory activity models suggested in favor of more negatively as well as more positively charged surface area descriptors for the better activity. The PLS analysis carried out on the descriptors of the Pf-PFT and Rat-PFT models suggested that among the parameters, the partially charged surface areas in the range -0.20 to -0.15 (PEOE_VSA-3) and -0.30 to -0.25 (PEOE_VSA-5), hydrophobicity (a_hyd, logP(o/w) and SlogP_VSA4), and electronic energy (PM3_Eele) of the molecules hold promise for modulating the Pf-PFT/R-PFT inhibitory activities of the compounds. This suggested the possibility of modulating the Pf-PFT/R-PFT inhibitory activities and bringing about selectivity in the THQ analogues for the malarial parasite enzyme.

Chemotherapeutic Potential of 2-[Piperidinoethoxyphenyl]-3-Phenyl-2H-Benzo(b)pyran in Estrogen Receptor- Negative Breast Cancer Cells: Action via Prevention of EGFR Activation and Combined Inhibition of PI-3-K/Akt/FOXO and MEK/Erk/AP-1 Pathways

Inhibition of epidermal growth factor receptor (EGFR) signaling is considered to be a promising treatment strategy for estrogen receptor (ER)-negative breast tumors. We have investigated here the anti-breast cancer properties of a novel anti-proliferative benzopyran compound namely, 2-[piperidinoethoxyphenyl]-3-phenyl-2H-benzo(b)pyran (CDRI-85/287) in ER- negative and EGFR- overexpressing breast cancer cells. The benzopyran compound selectively inhibited the EGF-induced growth of MDA-MB 231 cells and ER-negative primary breast cancer cell culture. The compound significantly reduced tumor growth in xenograft of MDA-MB 231 cells in nude mice. The compound displayed better binding affinity for EGFR than inhibitor AG1478 as demonstrated by molecular docking studies. CDRI-85/287 significantly inhibited the activation of EGFR and downstream effectors MEK/Erk and PI-3-K/Akt. Subsequent inhibition of AP-1 promoter activity resulted in decreased transcription activation and expression of c-fos and c-jun. Dephosphorylation of downstream effectors FOXO-3a and NF-κB led to increased expression of p27 and decreased expression of cyclin D1 which was responsible for decreased phosphorylation of Rb and prevented the transcription of E2F- dependent genes involved in cell cycle progression from G1/S phase. The compound induced apoptosis via mitochondrial pathway and it also inhibited EGF-induced invasion of MDA-MB 231 cells as evidenced by decreased activity of MMP-9 and expression of CTGF. These results indicate that benzopyran compound CDRI-85/287 could constitute a powerful new chemotherapeutic agent against ER-negative and EGFR over-expressing breast tumors.

Discovery of triazine mimetics as potent antileishmanial agents.

The World Health Organization has classified the leishmaniasis as a major tropical disease. The discovery of new compounds for leishmaniasis is therefore a pressing concern for the anti-infective research program. We have synthesized 19 compounds of triazine dimers as novel antileishmanial agents. Most of the synthesized derivatives exhibited better activity against intracellular amastigotes (IC50 ranging from 0.77 to 10.32 μM) than the control, pentamidine (IC50 = 13.68 μM), and are not toxic to Vero cells. Compounds 14 and 15 showed significant in vivo inhibition of 74.41% and 62.64%, respectively, in L. donovani/hamster model. Moreover, expansion of Th1-type and suppression of Th2-type immune responses proved that compound 14 stimulates mouse macrophages to prevent the progression of leishmania parasite. The molecular docking studies involving PTR1 protein PDB further validated the concepts involved in the design of these compounds. Among the investigated analogues, compound 14 has emerged as the potential one to enlarge the scope of the study.

Specific targeting of insulin-like growth factor 1 receptor signaling in human estrogen dependent breast cancer cell by a novel tyrosine-based benzoxazepine derivative.

The present study sought to investigate the in vitro and in vivo effects of a tyrosine-based benzoxazepine, 4-[4-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-3-ylmethyl]-phenol) [THBP] in human breast cancer cells, with a focus on determining its molecular target. THBP had growth inhibitory effect on MCF-7 and MDA-MD-231 cells. At IC(50) value (∼20 μM), THBP resulted in G1 arrest, decrease in cyclin D1 levels and induction of apoptosis of MCF-7 cells. Mechanistically, activation of caspase 8 contributes critically to the induction of apoptotic cell death as copresence of selective inhibition of caspase 8 effectively abrogates the cytotoxic effect of THBP in MCF-7 cells. Further, THBP increased pro-apoptotic protein, Bax; decreased anti-apoptotic protein, Bcl-2; and decreased mitochondrial membrane potential in MCF-7 cells, indicating involvement of an intrinsic pathway of apoptosis following caspase 8 activation. Out of the various growth factors/hormones, THBP selectively abrogated increased viability of MCF-7 cells by insulin-like growth factor 1 (IGF-1). Molecular docking studies revealed that THBP occupied the ATP binding pocket of IGF-1 receptor (IGF-1R). Accordingly THBP was found to inhibit IGF-1-induced phosphorylation of IGF-1R and insulin receptor substrate-1 (IRS-1) without inhibiting insulin signaling in MCF-7 cells. In athymic nude mice, compared with vehicle, THBP treatment significantly reduced the growth of MCF-7 xenograft tumors through inhibition of cancer cell proliferation as well as promotion of cell death that correlated with reduced phospho-IGF-1R levels. We suggest that interfering with the IGF-1R signaling by the benzoxazepine THBP offers a novel and selective therapeutic strategy for estrogen receptor-positive, postmenopausal breast cancer patients.

Topological descriptors in modelling antimalarial activity: N1-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine as prototype

The QSAR of antimalarial activity of two distinct series of N1-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl) piperazine analogues are investigated with DRAGON descriptors in order to rationalize their activity. Of these two series of compounds, one has amide characteristics and the other has amine characteristics. Both the analogues have shared radial centric information (ICR) as common modelling descriptor with increased centricity in the molecules as preferred feature for antimalarial activity. Apart from this, the models of amide analogues suggested in favor of distantly placed nitrogen(s) and unfavorable nature of carbonyl moieties adjacent to nitrogen in the varying portion of the molecule for the activity. Moreover, for these analogues, the regression models have preferred the lone pair electrons on heteroatoms (N and O) for purposes other than H-bonds for better activity. In case of amine analogues, the models suggested in favor of compact structural moieties in the varying parts of the molecule for improved activity. Also, for these analogues, hydrophobicity of the compound is an important factor for influencing activity. The variations in the models of amide and amine analogues are attributed to the characteristic functional differences of these analogues.