From Hit to Lead: Systematic Optimization of the Quinazolinedione Scaffold as Potent and Noncytotoxic Antimalarial Agents
Issued Date
2026-04-21
Resource Type
eISSN
24701343
Scopus ID
2-s2.0-105036418447
Journal Title
ACS Omega
Volume
11
Issue
15
Start Page
22796
End Page
22806
Rights Holder(s)
SCOPUS
Bibliographic Citation
ACS Omega Vol.11 No.15 (2026) , 22796-22806
Suggested Citation
Lohawittayanan D., Khulmanee T., Thima K., Chabang N., Yenjai W., Kanjanasirirat P., Schlaeppi P., Tantivess V., Phumisithikul T., Ratcha-in D., Chotsriluecha S., Chuchaisuwannasri D., Phanchana M., Pinthong N., Patrapuvich R., Charoensutthivarakul S. From Hit to Lead: Systematic Optimization of the Quinazolinedione Scaffold as Potent and Noncytotoxic Antimalarial Agents. ACS Omega Vol.11 No.15 (2026) , 22796-22806. 22806. doi:10.1021/acsomega.5c12006 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/116401
Title
From Hit to Lead: Systematic Optimization of the Quinazolinedione Scaffold as Potent and Noncytotoxic Antimalarial Agents
Corresponding Author(s)
Other Contributor(s)
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 (IC<inf>50</inf> = 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 IC<inf>50</inf> of 116 nM against P. falciparum 3D7. Crucially, this potent analogue and every compound in the series exhibited negligible cytotoxicity against human HepG2 cells (IC<inf>50</inf> > 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.