A series of 21 novel compounds containing a thiosemicarbazone moiety were designed and synthesised based on hit compound 1 from our in-house compound library screening. Most compounds showed potent antifungal activity in vitro against seven common pathogenic fungi. Notably, all compounds showed high potency against Candida glabrata 537 (MIC = ≤0.0156-2 µg/mL). Of note, compounds 5j and 5r displayed excellent antifungal activity against Candida krusei 4946 and Candida auris 922. Additionally, compounds 5j and 5r also showed high potency against 15 C. glabrata isolates with MIC values ranging from 0.0625 µg/mL to 4 µg/mL, with compound 5r being slightly superior to 5j. Moreover, compound 5r has certain effect against biofilm formation of C. glabrata. Furthermore, compound 5r has minimal cytotoxicity against HUVECs with an IC50 value of 15.89 µg/mL and no haemolysis at 64 µg/mL. Taken together, these results suggest that promising lead compound 5r deserves further investigation.
Keywords: Hydroxy-phenylhydrazone; antifungal; structure-activity relationship; synthesis; thiosemicarbazone.