Sulfonamide based pyrimidine derivatives combating parasite by inhibiting falcipains-2 and falcipains-3 as antimalarial agents.

In this report, we present the design and synthesis of a novel series of pyrimidine-tethered spirochromane-based sulfonamide derivatives aimed at combating drug resistance in malaria. The antimalarial effectiveness of these compounds was assessed . Structural validation of the synthesized compounds was conducted using mass spectrometry and NMR spectroscopy. Strong antimalarial activity against CQ-sensitive (3D7) and CQ-resistant (W2) strains of was demonstrated by the majority of the compounds. Notably, compounds SZ14 and SZ9 demonstrated particularly potent effects, with compound SZ14 showing IC values of 2.84 μM and SZ9 3.22 μM, indicating single-digit micromolar activity. The compounds exhibiting strong antimalarial activity were assessed through enzymatic tests against the cysteine protease enzymes of , falcipain-2 and falcipain-3. The results indicated that SZ14 and SZ9 inhibited FP-2 (IC values: 4.1 and 5.4 μM, respectively), and FP-3 (IC values: 4.9 and 6.3 μM, respectively). To confirm the compounds' specificity towards the parasite, we investigated their cytotoxicity against Vero cell lines, revealing strong selectivity indices and no significant cytotoxic effects. Additionally, hemolysis testing showed these compounds to be non-toxic to normal human blood cells. Moreover, predicted ADME parameters and physiochemical characteristics demonstrated the drug-likeness of the synthetic compounds. These collective findings suggest that sulfonamide derivatives based on pyrimidine-tethered oxospirochromane could serve as templates for the future development of potential antimalarial drugs.