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

  • ACS Omega. 2026 Apr 7;11(15):22796-22806. doi: 10.1021/acsomega.5c12006.
Duangporn Lohawittayanan  1  2 ,  Tachin Khulmanee  3  4 ,  Kanthinich Thima  4 ,  Napason Chabang  1 ,  Wanchalerm Yenjai  1 ,  Phongthon Kanjanasirirat  5  6 ,  Patrick Schlaeppi  1 ,  Varisa Tantivess  1 ,  Tanadej Phumisithikul  1 ,  Detchart Ratcha-In  1 ,  Sanisorn Chotsriluecha  1 ,  Dhanita Chuchaisuwannasri  1  7 ,  Matthew Phanchana  8 ,  Nattapon Pinthong  4 ,  Rapatbhorn Patrapuvich  3 ,  Sitthivut Charoensutthivarakul  1  2  6  9
Affiliations
  • 1. Innovative Molecular Discovery Laboratory (iMoD), School of Bioinnovation and Bio-based Product Intelligence, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
  • 2. Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
  • 3. Drug Research Unit for Malaria (DRUM), Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand.
  • 4. Department of Protozoology, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand.
  • 5. Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
  • 6. Excellent Center for Drug Discovery (ECDD), Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
  • 7. Samsenwittayalai School, Bangkok 10400, Thailand.
  • 8. Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand.
  • 9. Center for Neuroscience, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
PMID: 42040410 DOI: 10.1021/acsomega.5c12006
Abstract

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.

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