From Hit to Lead: Systematic Optimization of the Quinazolinedione Scaffold as Potent and Noncytotoxic Antimalarial Agents

The emergence of Plasmodium falciparum resistance to artemisinin-based therapies necessitates the urgent discovery of new antimalarials with novel scaffolds and mechanisms. The quinazolinedione scaffold, exemplified by the TCAMS hit TCMDC-125133, was identified as a promising, noncytotoxic starting point. Herein, we report a systematic lead optimization campaign commencing from a simplified and synthetically tractable analogue, compound 9 (IC50 = 586 nM), which was previously reported by our group. A focused library of 57 novel derivatives was designed and synthesized via a concise 5-step route to systematically explore the structure–activity relationships of the terminal phenyl side chain and the quinazolinedione core. Our investigation revealed two critical findings: (i) the 3,4-difluorophenyl side chain was optimal for potency, and (ii) substitution of the core with small, electron-withdrawing halogens was highly beneficial. This strategy led to the discovery of compound 53 which pairs a 6,7-difluoro core with a 3,4-difluorophenyl side chain demonstrating a potent IC50 of 116 nM against P. falciparum 3D7. Crucially, this potent analogue and every compound in the series exhibited negligible cytotoxicity against human HepG2 cells (IC50 > 20 μM) indicating a high selectivity. This work validates the 7-halogenated quinazolinedione scaffold as a promising and selective chemotype for further antimalarial drug development.