Design, synthesis, spectroscopic characterization, in vitro tyrosinase inhibition, antioxidant evaluation, in silico and kinetic studies of substituted indole-carbohydrazides

In the current study, twenty-five indole-carbohydrazide derivatives linked to different aryl substitutions were rationally designed and synthesized. The structures of all derivatives were confirmed using different spectroscopic techniques including H-1 NMR, C-13 NMR, Mass spectrometry, and elemental analysis. The tyrosinase inhibitory activities of all synthetic compounds exhibited IC50 values in the range of 0.070 to > 100 mu M. Structure-activity relationships showed that compounds 4f (R = 4-OH, IC50 = 0.070 mu M), 8f (R = 4-OH, IC50 = 0.072 mu M), and 19e (IC50 = 0.19 mu M) with para-OH substituent at the R position was found to be the most active members of all three tested series. Kinetic studies exhibited that compounds 4f, 8f, and 19e are mixed-type inhibitors. Furthermore, toxicity and cell-based anti-melanogenesis assessments were performed on the most potent derivatives and it was shown that 4f, 8f, and 19e had no toxicity at 8 mu M and reduced the percent of melanin content to 68.43, 72.61, 73.47 at 8 mu M, respectively. In silico analyses of absorption, distribution, metabolism, and excretion (ADME) profile of synthesized compounds showed that these molecules followed drug-likeness rules and acceptable predictive ADMET features. Results of the docking study were almost in line with biological results with ChemPLP values of 53.56 to 79.33. Also, the docking study showed the critical interactions of potent inhibitors with the active site of the enzyme which affects the potency of the synthesized hybrids. Based on molecular dynamic simulations, compound 4f exhibited pronounced interaction with the critical residues of the tyrosinase active site so that the indole ring participated in H-bond interaction with Gly281 and 4-hydroxy benzylidene recorded another H-bond interaction with Asp289 plus hydrophobic interactions with Phe292. Hydrazide linker also exhibited three H-bond interactions with His263 and Gly281.

Automated summary

In this study, 25 indole-carbohydrazide derivatives were synthesized and their structures were confirmed using spectroscopic techniques. These derivatives exhibited inhibitory activity against tyrosinase, with compounds 4f, 8f, and 19e being the most active. The docking study revealed the critical interactions of these potent inhibitors with the active site of the enzyme. Additionally, the derivatives showed no toxicity and reduced melanin content in cell-based assays.