Synthesis, quantum chemical calculations, molecular docking, dynamic simulations and ADME predictions of cyclopropylmethyl substituted indole-based hydrazones
Abstract
The cyclopropylmethyl substituted indole hydrazone (CPMIH) derivatives were synthesised and characterised using FT-IR and 1H NMR spectroscopic techniques. Their molecular structures and electronic properties were computed by Density Functional Theory (DFT) at the B3LYP/6-31G+(d,p) level theory via Gaussian 16. The molecular parameters of the synthesised hydrazones suggest conjugation across the molecules with possible receptor interaction at the most negative electrostatic potential. The FMO analysis with global reactivity descriptors shows good kinetic stability. The theoretically predicted vibrational spectrum of CPMIH 1 was validated by comparison with the experimental FT-IR spectrum, revealing a strong correlation between the calculated and observed frequencies. Molecular docking studies revealed good binding affinities and interaction profiles with the active site of the Serotonin subtype 5-hydroxytryptamine receptor 2B (5-HT2B). Furthermore, pharmacokinetic, drug-likeness potential, blood–brain barrier (BBB) permeability and human intestinal absorption (HIA) were predicted and compared with the effect of the addition of cyclopropylemthyl substitution through in silico ADME profiling using the SwissADME web tool and the Boiled-egg model. These results offer a valuable basis for the rational design of new 5-HT2B receptor inhibitors with suitable drug-like properties to become a computationally prioritised candidate for in vitro and in vivo validation.
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