Synthesis and primary evaluation of quinoxalinone derivatives as potent modulators of multidrug resistance

Abstract

P-glycoprotein-mediated drug efflux from cells is believed to be an important mechanism in multidrug resistance (MDR) in cancer chemotherapy. The identification and development of P-glycoprotein inhibitors with high potency and low cytotoxicity holds great promise for overcoming MDR. A series of quinoxalinone derivatives were synthesized and evaluated primarily for their antiproliferative effect and MDR reversal activity in in vitro assay systems. Biological assays demonstrated that the compounds were, in general, endowed with good activity as Pglycoprotein inhibitors. Among them, compounds 10 and 16, which showed the highest MDR reversal activity without significant cytotoxicity, displayed potent Pglycoprotein inhibition activities and may be worthy of further research as potential adjunctive agents for tumor chemotherapy.

Quinoxaline-based inhibitors of Ebola and Marburg VP40 egress

“…In most cases, the quinoxaline thiol 55 was commercially available but in a few examples (R 1 = CF 3 and Et) we prepared this thiol by converting congeners 54 (R 1 = CF 3 and Et) using P 2 S 5 and pyridine. 37 Compound 54 where R 1 = CF 3 was prepared by reaction of o -phenylenediamine with ethyl trifluoropyruvate 38 and 54 where R 1 = Et is commercially available.…”

Synthesis of a New Polyfunctionalised Pyrimidine-4-carboxylate and Its Application for the Construction of a Series of Pyrimidine Derivatives

“…We describe here the highly regioselective synthesis of 5-substituted acyl 2-phenylpyrimidine-4-carboxylate 2 (Figure 1) from the cyclocondensation of precursor 1 with benzamidine hydrochloride. Further, we have also explored the synthetic potential of polyfunctionalised pyrimidine-4carboxylate 2 from the reaction with hydrazines, 13,14 hydroxylamine hydrochloride, 15 and 1,2-phenylenediamine 16 under mild conditions. This allowed the efficient synthesis of pyrimido [4,5-d]pyridazin-8-one-5-carboxylate and its corresponding carbohydrazide and N-acylhydrazone (NAH) derivatives, pyrimido [4,5-d] [1,2]oxazin-8-one and the corresponding carbohydrazide derivative, 3-pyrimidinylquinoxaline-2-one and their corresponding carbohydrazide, and two pyrimidine hydroxyimino derivatives.…”

Pharmacological Profile of Quinoxalinone

“…Biological assays demonstrated that the compounds 81a-t ( Figure 33 and Table 12) were, in general, endowed with good activity as P-glycoprotein inhibitors. Among them, compounds which showed the highest MDR reversal activity without significant cytotoxicity displayed potent P-glycoprotein inhibition activities and may be worthy of further research as potential adjunctive agents for tumor chemotherapy [68].…”