Carboxamide appended quinoline moieties as potential anti-proliferative agents, apoptotic inducers and Pim-1 kinase inhibitors

Abstract

The targeted approach of protein kinases (PKs), as PKs are the main regulators of cell survival and proliferation, has been a promising strategy for treatments for cancer. Here we analyze the potential of quinoline-carboximide derivatives for four cell lines: MCF-7, CACO, HepG-2 and HCT-116 as anticancer agents. 3e, 4b, 11b and 13d derivatives showed good anti-proliferative activities in comparison to the reference standard Doxorubicin, against the four cell lines tested. They have been chosen for further studies. First of all, the IC50 value surveys were carried out to ensure the protection of our hits and demonstrate that the cytotoxic effect (IC50 > 113 μM) is highly selective on normal human cells (WI-38). Secondly, apoptosis was accomplished by down-regulation of Bcl-2 and up-regulation of BAX and Caspase-3 by these active compounds. Also, the Pim-1 inhibitory activity of the active hybrids was done, which indicate that compound 3e was the most active with percentage of inhibition 82.27% and IC50 equal 0.11 when compaired to SGI-1776 as a reference standered. In addition, the in silico assessment of ADME properties, all of the strongest compounds are orally bioavailable without blood brain barrier penetration.

Novel fluorinated pyrazole-based heterocycles scaffold: cytotoxicity, in silico studies and molecular modelling targeting double mutant EGFR L858R/T790M as antiproliferative and apoptotic agents

“…Caspase 3 is the most important protein in the caspase family that is highly conserved and functions as a central apoptosis regulator in multicellular organisms. Thus, it has become an attractive strategy for the treatment of cancer in critical regulators of apoptosis to induce apoptosis in cancer cells [11,[15][16][17][18][19]. The molecular mechanisms used by cancer cells for apoptosis are multifarious [20].…”

In Vitro Antimicrobial Evaluation, Single-Point Resistance Study, and Radiosterilization of Novel Pyrazole Incorporating Thiazol-4-one/Thiophene Derivatives as Dual DNA Gyrase and DHFR Inhibitors against MDR Pathogens

“…Hybridizing two or more scaffolds in one molecule to create a new hybrid molecule is useful for developing new therapeutic agents. − Based on these things mentioned above, herein, we report the design and synthesis of novel series of pyrazole derivatives incorporating thiazol-4-one/thiophene in one molecule via conventional synthetic approaches to obtain new pyrazole derivatives (Figure ). The new hybrid molecules were screened against three Gram-positive, three Gram-negative bacteria, and two Candida albicans isolates.…”

Upregulation of BAX and caspase‐3, as well as downregulation of Bcl‐2 during treatment with indeno[1,2‐b]quinoxalin derivatives, mediated apoptosis in human cancer cells

“…Nowadays, heterocycles are considered promising compounds for the development of novel chemotherapeutic agents, [ 12–19 ] and one of these heterocycles is quinoxaline. [ 20,21 ]…”

“…[10] Bax and Bcl-2 are, respectively, apoptotic and antiapoptotic proteins, and the ratio of these two proteins determines the occurrence of cell apoptosis. [11] Nowadays, heterocycles are considered promising compounds for the development of novel chemotherapeutic agents, [12][13][14][15][16][17][18][19] and one of these heterocycles is quinoxaline. [20,21] Additionally, molecular hybridization is a contemporary concept that is gaining popularity worldwide in drug design and development.…”