Design, synthesis, in silico and antiproliferative evaluation of novel pyrazole derivatives as VEGFR-2 inhibitors.

As the blockade of the VEGFR-2 signaling pathway is a viable approach in cancer therapy, the present study focuses on a series of pyrazole based VEGFR-2 inhibitors that were designed on the basis of the hybridization approach, supported by docking and in silico computational studies. The designed compounds were synthesized through facile synthetic methods and the structures were confirmed by 1 H NMR, 13 C NMR, MS and elemental analysis. The compounds were screened for in vitro antiproliferative activity against the HT-29 (human colon cancer) and MCF-7 (human breast cancer) cell lines by MTT assay. The compounds were also studied for in vitro inhibitory activity against VEGFR-2 kinase. Among all the tested compounds, compound 6h emerged as a potent agent in the antiproliferative study against HT-29 and MCF-7 cells, with IC50 values of 2.36 and 6.59 µM, respectively. Moreover, the same compound exhibited the highest VEGFR-2 inhibitory activity with an IC50 value of 1.89 µM. In docking studies, the designed compounds showed similar and essential key interactions as those of known VEGFR-2 inhibitors. The present study may lead to new molecules in the development of anticancer agents targeting VEGFR-2.

Design, synthesis, in silico and in vitro evaluation of thiophene derivatives: A potent tyrosine phosphatase 1B inhibitor and anticancer activity.

A series of novel methyl 4-(4-amidoaryl)-3-methoxythiophene-2-carboxylate derivatives were designed against the active site of protein tyrosine phosphatise 1B (PTP1B) enzyme using MOE.2008.10. These molecules are also subjected for in silico toxicity prediction studies and considering their corresponding drug scores, it implied that, the molecules are promising as anticancer agents. The designed compounds were synthesized by using suitable methods and characterized. They were subjected to inhibitory activity against PTP1B and in vitro anticancer activity by MTT assay. Most of the tested compounds showed potent inhibitory activity against PTP1B, among the compounds tested, compound 5b exhibited the highest activity (IC50=5.25µM) and remarkable cytotoxic activity at 0.09µM of IC50 against the MCF-7 cell line. In addition to this, compound 5c also showed potential anticancer activity at 2.22µM of IC50 against MCF-7 and 0.72µM against HepG2 cell lines as well as PTP1B inhibitory activity at IC50 of 6.37µM.

Design, Synthesis and Biological Evaluation of Novel Urea and Thiourea Bearing thieno[3,2-d]-pyrimidines as PI3 Kinase Inhibitors.

BACKGROUND: Phosphatidylinositol-3-kinase α (PI3Kα) is a ubiquitous intracellular enzyme, mainly involved in intracellular signaling pathways, promotes cellular growth, proliferation, and differentiation. Therefore, inhibition of PI3K can be a hotspot in molecular targeted therapy for the treatment of cancer. METHODS: The present research work involves molecular docking studies performed to screen derivatives of urea and thiourea bearing thieno [3,2-d]-pyrimidines against the active site of PI3K enzyme using MOE.2008.10. The designed structures (6a-f) and (7a-j) were synthesized by the facile synthetic methods and evaluated for their anticancer activity against HT-29 and MCF-7 cell lines and inhibitory activity against PI3Kα enzyme. RESULTS: Among the tested compounds, 4-(4-(2-(3-(pyrimidin-2-yl)thioureido)ethyl)piperazin-1-yl)thieno[3,2- d]pyrimidine-6-carboxamide (7f) showed the highest anticancer activity against HT-29 and MCF-7 cell lines with IC50 values of 2.18 µM and 4.25 µM, respectively. Further, the same compound also exhibited potent PI3Kα inhibitory activity with IC50 value of 1.26 µM. CONCLUSION: Docking studies supported the initial pharmacophoric hypothesis and suggested a mode of interaction at the active binding site of PI3Kα, demonstrating that the target compounds were potential inhibitory agents for cancer therapy.

A novel medium size lactam ring analoges as antibacterial agents: Synthesis, biological evaluation and molecular docking studies.

A novel series of medium size (S)-3-alkyl-3,4,6,7-tetrahydro-1H-benzo[e][1,4]diazonine-2,5-dione (6a-f) analogues were synthesized from (E)-3-(2-nitrophenyl)acrylicacid (2) reacting with various amino acid esters using Di-isopropyl Carbodiimide as a coupling agent. The final cyclization is carried out by using reagent 1-Ethyl-3(3-dimethylaminopropyl) Carbodiimide Hydrochloride. The synthesized compounds have been supported by Mass, 1H-NMR and 13C-NMR. Further antibacterial studies were conducted, where some molecules are noticed with potent activity, especially molecule 6d shown highest activity which was also supported by molecular docking studies. All final molecules were docked with enzyme peptide deformylase to determine the probable binding conformation.

Design, synthesis, in silico toxicity prediction, molecular docking, and evaluation of novel pyrazole derivatives as potential antiproliferative agents.

A new series of pyrazole derivatives were designed by docking into vascular endothelial growth factor receptor-2 (VEGFR-2) kinase active site. The designed compounds were synthesized and evaluated for in vitro antiproliferative activity against HT-29 colon and PC-3 prostate cancer cell lines, and angioinhibitory activity in chorioallantoic membrane (CAM) model. Based on the obtained antiproliferative activity results of in vitro and CAM assay, compounds 4b, 4c, 4f, 5b, 5c and 5f were selected, and tested for anticancer activity using in vivo ehrlich ascites carcinoma (EAC) bearing mice. Compound 5c showed the highest in vitro antiproliferative activity against HT-29 and PC-3 with IC50 values of 6.43 µM and 9.83 µM respectively and comparable to reference drug Doxorubicin. Results of in vivo anticancer activity revealed that compound 5c showed the highest percentage increase in life span ( %ILS), and mean survival time (MST) with 75.13 % and 32.4 ± 0.53 days respectively. Moreover, compound 5c demonstrated significant reduction of microvessel density (MVD) in CAM assay. In silico prediction of toxicities, and drug score profiles of designed compounds are promising. A correlation made between the results obtained by antiproliferative study and molecular docking studies suggest that the synthesized compounds may be beneficial as molecular scaffolds for antiproliferative activity.