Design,Synthesis And Activity Evaluation Of Novel Quinoxalinone Derivatives

Malignant tumor and bacterial infections are serious threats to human health and lives. Furthermore the ubiquitous side effects of curative drugs and tumor/bacterium multidrugs resistane to chemotherapeutic agents have been implicated as major obstacle in effective chemotherapy of these two diseases. So it is extremely urgent to develop new anticancer and antimicrobial agents. With the constant detection of new targets for cancer and bacterial infection treatments in recent years, the structure and mechanism-based drug design has become the mainstream of targeted anticancer and antibacterial drug discovery. Many of these kinds of drugs are currently undergoing clinical trials and shows better specificity and lower toxicity than the traditional chemotherapy drugs.Heterocyclic quinoxalinone and its derivatives are very important compounds which can be used as anticancer agents, antimicrobial (or antifungal) agents, HIV-1reverse transcriptase inhibitors, and antithrombotic agents, etc, showing wide applications prospects. Based on the structures of known inhibitors and binding modes of these compounds in complex with EGFR、MMP-2and HDAC, we designed and synthesized three series of45quinoxalinone compounds following the preliminary work of this group. And preliminary activity assay was carried out in vitro.The first series of compounds were synthesized starting from1,2-diaminobenzene through a reaction sequence including cyclization, N-methylation, Friedel-Crafts acylation condensation, and so on.The second and third series of compounds were synthesized starting from1,2-diaminobenze-ne through a reaction sequence including cyclization, N-methylation, Friedel-Crafts acylation condensation, saponification, hydroxylamine solutions and so on. All the structures of target compounds were identified by ESI-MS and HNMR spectras.The newly synthesized compounds were assayed for the inhibitory activities on MMP-2and HDAC(HDAC1,2). The test results demonstrated that these inhibitors didn’t showed significant inhibitory activities on MMP-2, while three compounds from series C showed highly selective inhibition against HDAC (C6, IC5o=2.442±0.78μM)。These target compounds were also assayed for their anti-proliferation activity towards SKOV3and HCT116cells. MTT method was employed and the result showed that several of these compounds did have potential anti-proliferative activity, of which compound B1can inhibit proliferations of these two cells with IC50value approxamate170μM.The antibacterial activity test result showed that only compound BIO exhibits some antibacterial activity in vitro. Although its activity is much lower than the positive control drugs, it is also worthy of further study.In conclusion, three series of novel quinoxalinone-based inhibitors were designed and synthesized. Preliminary enzymes inhibition activity and anti-proliferative activity assay results showed that some compounds possess potential inhibitory activity. Although their anticancer mechanism is not very clear, they are still a class of applied research prospects lead compounds for the development of a new generation of targeted anticancer drugs and antibacterial agents.