Development of substituted 2-(4-(sulfonyl)piperazin-1-yl)quinazoline molecular hybrids as a new class of...

The rapid emergence of drug resistance makes malaria elimination a global challenge despite the prevalence of artemisinin-based combination therapies (ACTs), thus highlighting the urgent need for the development of new antimalarials with novel modes of action. The present study aimed to develop new quinazoline hybrid antimalarials using bioactive small building blocks. The antimalarial activity results revealed that most molecular hybrids have IC₅₀ values below 10 µM for the drug-sensitive Pf3D7 strain. The study identified molecular hybrids 19, N-(2-chloro-4-((4-(4-(((tetrahydrofuran-2-yl)methyl)amino)quinazolin-2-yl)piperazin-1-yl)sulfonyl)phenyl)acetamide and 27, 2-(4-((2-nitrophenyl)sulfonyl)piperazin-1-yl)-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinazoline as potent antimalarials with an IC₅₀ value of 3.4 µM and 2.9 µM against Pf3D7, respectively. The cytotoxicity investigation against mammalian A549 cells and activated macrophages derived from THP1 monocytes revealed that the compounds were relatively non-cytotoxic, and their antimalarial activity was not associated with cytotoxicity. In silico studies were conducted to predict plausible drug targets of the compounds, and the results suggested that the antimalarial activity of the compounds may be due to the inhibition of zinc metalloprotease PfFLN, with concurrent inhibition of cysteine proteases PfFP2 and PfFP3. The MM-GBSA analysis revealed that the binding free energies of 19 and 27 with PfFLN were -50.3223 and -51.5066 kcal mol^-1, respectively. The predicted ADME properties of the compounds fall within the Schrödinger range, which encompasses 95% of all known medications. The study thus emphasised the significance of the molecular hybridisation approach and highlighted compounds 19 and 27 as potent hit molecules that could be further optimised for the development of new antimalarials.