Design, synthesis and biological evaluation of novel diazaspirodecanone derivatives containing piperidine-4-carboxamide as chitin synthase inhibitors and antifungal agents

Abstract

A series of novel 2-oxo-(1-oxo-2,8-diazaspiro[4.5]decane-8-yl)ethylpiperidine carboxamide derivatives were designed, synthesized and characterized by ¹H NMR, ¹³C NMR and HRMS spectroscopy. All eighteen newly prepared compounds were evaluated for their inhibition against chitin synthase (CHS) and antifungal activities in vitro. The enzyme assay revealed that compound 5h showed excellent inhibitory activity against CHS with IC₅₀ value of 0.10 mM, and the compounds 5b, 5d and 5q showed good inhibition against chitin synthase with IC₅₀ values of 0.13 mM, 0.18 mM and 0.15 mM, respectively, while IC₅₀ value of ployoxin B was 0.08 mM. Meanwhile, the others of these compounds exhibited moderate inhibition potency against chitin synthase. The antifungal assay showed compound 5h had excellent antifungal activity compared with the control drugs fluconazole and polyoxin B against these tested strains including C. albicans, A. fumigatus, C. neoformans and A. flavus. Its excellent antifungal activity was consistent with its excellent chitin synthase inhibition. Compound 5k and 5l against C. albicans were comparable with fluconazole, and they showed strong antifungal potency against A. flavus with MIC values of 0.07 mmol/L and 0.13 mmol/L respectively. Compound 5m had similar MIC value against A. fumigatus to fluconazole. The phenomenon that compounds 5b, 5d and 5q that showed good enzymatic inhibition didn't exert good antifungal activity, while compounds 5k, 5l and 5m that showed moderate chitin synthase inhibition exhibited excellent antifungal activity was discussed. Furthermore, the trial of drug combination showed that compounds had synergistic effects or additive effects with fluconazole against tested fungi which also verified that these designed compounds targeted different targets from that of fluconazole. Additionally, the antibacterial trial showed that all synthesized compounds had little potency against tested bacteria strains. These results indicated that the designed compounds were potential chitin synthase inhibitors and had selectively antifungal activities.

Keywords: 2,8-diazaspiro[4.5]decane-1-one; Antimycotics; Bio-evaluation; Drug design.