Evaluation of Fifteen 5,6-Dihydrotetrazolo[1,5-c]quinazolines Against Nakaseomyces glabrata: Integrating In Vitro Studies, Molecular Docking, QSAR, and In Silico Toxicity Assessments

<i>Nakaseomyces glabrata</i> (<i>Candida glabrata</i>), the second most prevalent Candida pathogen globally, has emerged as a major clinical threat due to its ability to develop high-level azole resistance. In this study, two new 5,6-dihydrotetrazolo[1,5-<i>c</i>]quinazoline derivatives (<b>c11</b> and <b>c12</b>) were synthesized and characterized using IR, LC-MS, ¹H, and ¹³C NMR spectra. Along with 13 previously reported analogues, these compounds underwent in vitro antifungal testing against clinical <i>N. glabrata</i> isolates using a serial dilution method (0.125-64 mg/L). Remarkably, compounds <b>c5</b> and <b>c1</b> exhibited potent antifungal activity, with minimum inhibitory concentrations of 0.37 μM and 0.47 μM, respectively-about a 20-fold improvement in μM concentration over standard drugs like amphotericin B, caspofungin, and micafungin. A detailed structure-activity relationship analysis revealed crucial molecular features enhancing antifungal potency. Extensive molecular docking studies across 18 protein targets explored potential binding pockets and affinities of the lead compounds. A robust 3D-QSAR model, incorporating molecular descriptors Mor26m and Mor29e, displayed good predictive ability for antifungal activity. In silico predictions indicated an absence of herbicidal effect, negligible environmental toxicity (to honeybees, avian species, and aquatic organisms), and mild human toxicity concerns for these compounds. This comprehensive approach aims to develop novel and effective antifungal compounds against the clinically relevant pathogen <i>N. glabrata</i>.