DESIGN AND SYNTHESIS OF NEW QUINAZOLIN-4(3H)-ONE HYBRIDS AS DUAL INHIBITORS OF TUBULIN AND DIHYDROFOLATE REDUCTASE

New strategies are needed for fighting cancer with the goal to improve efficacy of anti-cancer therapy and to limit the onset of drug resistance. Indeed, cancer cells are able to set cellular mechanisms for survival and multiple pathways support their survival. The inhibition of one pathway may then result in the activation of an alternative pathway. One strategy useful for combatting this phenomenon is represented by multi-target drugs. Herein we will present our work aim at identifying new anticancer compounds, which combine dihydrofolate reductase (DHFR) properties with tubulin inhibition. DHFR is a key enzyme involved in the synthesis of raw material for cell proliferation and the inhibition of tubulin protein family is able to suppress mitotic spindle dynamics and causes mitotic arrest and cell death. 1,2 To identify compounds able to simultaneously recognize the above-mentioned targets and using a molecular modelling approach, we designed a small library of potential DHFR/tubulin inhibitors. The quinazolin-4(3H)-one moiety is a common scaffold of DHFR and tubulin inhibitors and therefore it was select as starting pharmacophore. 2,3 Specifically, we designed compounds 1a-n, and performed docking studies on both tubulin and DHFR, in comparison with colchicine (a tubulin inhibitor reference compound) and LIH, a lipophilic antifolate. The docking results showed that seven compounds (1h-n), characterized by a 2-styryl group in the quinazolinone moiety, exhibited a good interaction with both tubulin and DHFR active sites with score values in the range of -10.7 ‒ -10.2 and -11.0 ‒ -9.9 kcal/mol, respectively. Among all, compound 1k emerged as the most interesting one, showing a potential good affinity for both enzymes. Building on these in silico results, we synthetized the whole compound series. Future preclinical studies are ongoing to confirm the DHFR and tubulin inhibition properties and therefor their efficacy on cancer cells cytotoxic activity.