Search

A series of 5-(4-pyridyl)-1,2,4-triazoles hybrids with acetophenones and their oxime derivatives was rationally designed and synthesized as epidermal growth factor receptor (EGFR) kinase inhibitors. Initially, drug Likeness and pharmacokinetics properties of the prepared compounds were evaluated. Afterward, the prepared compounds were in vitro screened for their ability to inhibit the growth of the NCI-60 human cancer cell lines where certain compounds showed moderate activity. Compounds 4e and 5b emerged as the most potent compounds in this series were further tested for their EGFR enzyme inhibition activity. They showed IC50 values of 0.14 and 0.18 µM, respectively, in comparison with Gefitinib as a reference with an IC50 value of 0.06 µM. Docking of compounds 4e and 5b into the binding site of EGFR tyrosine kinase was performed to explains their possible binding mode and to compare it with known inhibitors. Moreover, molecular dynamic simulations were estimated for deeper understanding of the binding mode of compounds 4e and 5b at the binding site of EGFR tyrosine kinase. The findings indicated that the novel ligands 4e and 5b were stable in the EGFR tyrosine kinase active site.

The structure-based design of some CDK2 inhibitors with a 3-(benzylidene)indolin-2-one scaffold as potential anticancer agents was realized. Target compounds were obtained as E/Z mixtures and were resolved to corresponding E- and Z-diastereomers. In silico studies using MOE 2019.01 software revealed better docking on the targeted enzyme for the Z-diastereomer compared to the E-one. A time-dependent kinetic isomerization study was carried out for the inversion of E/Z diastereomers in DMSO-d6 at room temperature, and were found to obey the first order kinetic reactions. Furthermore, a determination of the kinetic inter-conversion rate order by graphical analysis method and calculation of the rate constant and half-life of this kinetic process were carried out. For the prediction of the stability of the diastereomer(s), a good multiple regression equation was generated between the reaction rates of isomerization and some QM parameters with significant p value.

In an attempt to obtain new candidates with potential anti-inflammatory activity, two series of 1,3,4-oxadiazole based derivatives (8a-g) and 1,2,4-triazole based derivatives (10a,b and 11a-g) were synthesized and evaluated for their COX-1/COX-2 inhibitory activity. In vitro assays showed potent COX-2 inhibitory activity and selectivity of the novel designed compounds (IC

The structure-based design of some CDK2 inhibitors with a 3-(benzylidene)indolin-2-one scaffold as potential anticancer agents was realized. Target compounds were obtained as

Made available in DSpace on 2018-12-11T16:50:40Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-01-01 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Biotechnology and Biological Sciences Research Council Three series of azole piperazine derivatives that mimic dicyclotyrosine (cYY), the natural substrate of the essential Mycobacterium tuberculosis cytochrome P450 CYP121A1, were prepared and evaluated for binding affinity and inhibitory activity (MIC) against M. tuberculosis. Series A replaces one phenol group of cYY with a C3-imidazole moiety, series B includes a keto group on the hydrocarbon chain preceding the series A imidazole, whilst series C explores replacing the keto group of the piperidone ring of cYY with a CH2-imidazole or CH2-triazole moiety to enhance binding interaction with the heme of CYP121A1. The series displayed moderate to weak type II binding affinity for CYP121A1, with the exception of series B 10a, which displayed mixed type I binding. Of the three series, series C imidazole derivatives showed the best, although modest, inhibitory activity against M. tuberculosis (17d MIC = 12.5 μg/mL, 17a 50 μg/mL). Crystal structures were determined for CYP121A1 bound to series A compounds 6a and 6b that show the imidazole groups positioned directly above the haem iron with binding between the haem iron and imidazole nitrogen of both compounds at a distance of 2.2 Å. A model generated from a 1.5 Å crystal structure of CYP121A1 in complex with compound 10a showed different binding modes in agreement with the heterogeneous binding observed. Although the crystal structures of 6a and 6b would indicate binding with CYP121A1, the binding assays themselves did not allow confirmation of CYP121A1 as the target. School of Pharmacy and Pharmaceutical Sciences Cardiff University Department of Medicinal Chemistry Faculty of Pharmacy Assiut University Department of Life Sciences University of Modena and Reggio Emilia, Via G. Campi 183 Faculty of Pharmaceutical Sciences UNESP – Univ Estadual Paulista, Araraquara Manchester Institute of Biotechnology School of Chemistry University of Manchester Faculty of Pharmaceutical Sciences UNESP – Univ Estadual Paulista, Araraquara CNPq: 140079/2013-0 FAPESP: 2011/21232-1 Biotechnology and Biological Sciences Research Council: BB/I019227/1 Biotechnology and Biological Sciences Research Council: BB/K001884/1