Design, synthesis, molecular docking and DFT studies on novel melatonin and isatin based azole derivatives

Abstract

In order to address the pressing demand for newer broad-spectrum antifungal medicines with enhanced activity, computer modelling was utilised to rationally develop newer antifungal azole-based drugs. Based on the drug and active sites of the Lanosterol 14 alpha-Demethylases (LAD) of the prominent fungal pathogen Candida albicans interaction, Novel triazole-linked melatonin and isatin derivatives 7a-d and 8a-d were synthesised using bioisosterism. Besides the experimental synthesis and subsequent characterization, the present study focused on obtaining optimised geometries, frequency calculations, and TD-DFT studies of the synthesised molecules. We also performed molecular docking studies to explore the inhibitory ability of the synthesised compounds against the active sites of the Lanosterol 14 alpha-Demethylases (LAD) of the prominent fungal pathogen Candida albicans. The binding interactions resulted in positive findings, demonstrating the involvement of the synthesised compounds in the suppression of fungal growth. Comparative analysis of the binding potential of the synthesised molecules and commercially available drug fluconazole revealed a remarkable note: the docking scores for the designed drugs 7b, 7c, and 8c are much greater than those of the fluconazole molecule. The in silico study of the designed series of drug molecules serves as an important guideline for further exploration in the quest for potent antifungal agents.

Fig. 1. Melatonin, triazole, and isatin-based antifungal agents, mapped to the designed target compound.

Scheme 1. Synthesis of propargylated derivative of melatonin 1 1(1 eq), NaH (1 eq).

Scheme 2. Synthesis of 2-azidoethyl-Isatins derivatives (5a–d).

Scheme 3. Synthesis of N-alkylazido-hydxoxyiminoisatins derivatives (6a–d).

Scheme 4. Synthesis of target compound 7a–d and 8a–d using click reaction.

Fig. 2. Optimised geometrical structures of the designed molecules; 7b, 7c and 8c.

Fig. 3. The best docked molecules 7b, 7c, and 8c to Lanosterol 14 alpha-Demethylases protein with the highest docking score of −11.1 kcal mol⁻¹ (7b), −11.0 kcal mol⁻¹ (7c) and −11.6 kcal mol⁻¹ (8c) as compared with standard drug fluconazole (−8.2 kcal mol⁻¹).

Fig. 4. Detailed depiction of molecular interaction of the ligand molecules (7b, 7c, and 8c) having highest binding energy, with various amino acid residue in the binding pocket of the protein Lanosterol 14 alpha-Demethylases of prominent fungal pathogens Candida albicans.

Fig. 5. The docking score for the synthesised molecules i.e., 6, 7a–d, 8a–d and commercially available fluconazole drug with reference to their binding energy.