Novel Paclobutrazol Derivatives as Potential Antifungal and CGRP Receptor Modulators: Synthesis and a Computational Assessment

Background/Objectives: Escalating resistance to existing antifungal compounds necessitates development of novel bioactive molecules with innovative mechanisms. Paclobutrazol, a triazole-containing plant growth regulator with modest antifungal activity, presents a structurally versatile scaffold amenable to derivatization. This study investigated whether strategic structural modifications could enhance antifungal potency and reveal broader therapeutic applications through integrated computational approaches. Methods: Twenty-six novel paclobutrazol derivatives were synthesized via etherification or esterification and characterized through NMR spectroscopy (¹H, ¹³C, ¹⁹F), IR spectroscopy, and mass spectrometry. Computational assessment employed CropCSM for toxicity prediction, pdCSM-GPCR for G protein-coupled receptor affinity estimation, MolPredictX for pathogenic target activity probability, CB-Dock2 for molecular docking, and pkCSM for ADME properties and drug-likeness evaluation. Results: Compound 26, featuring naphthyl substitution, demonstrated strong binding to sterol 14-alpha demethylase (-10.8 kcal/mol), calcitonin gene-related peptide type 1 receptor (-11.1 kcal/mol), extracellular calcium-sensing receptor (-10.9 kcal/mol), and metabotropic glutamate receptor 4 (-10.4 kcal/mol), with CGRP1R affinity comparable to approved antagonist rimegepant (-11.3 kcal/mol). Compounds 18 and 19, containing nitro groups, were the only substances predicted to exhibit AMES toxicity. Multiple derivatives showed activity against fungal, bacterial, parasitic, and viral targets. Compounds 20-22 displayed favorable drug-like properties with balanced physicochemical parameters. Conclusions: This work establishes paclobutrazol as a viable scaffold for therapeutic development beyond traditional antifungal applications. The analysis suggests potential utility in migraine and pain management through CGRP receptor modulation, calcium homeostasis disorders via calcium-sensing receptor targeting, neuroendocrine conditions through somatostatin receptor type 5, and inflammatory diseases via prostaglandin D2 receptor 2. These findings provide a framework for repurposing agricultural compounds in drug discovery, though further experimental validation is required.