3-substituted indole derivatives as potential drug candidates: Lipophilicity, solubility, drug-likeness, and VEGFR2 binding studies.

Abstract

Improving key physicochemical and pharmacokinetic properties such as lipophilicity, water solubility, pharmacokinetics, and drug-likeness is crucial for evaluating a compound's absorption, distribution, metabolism, and excretion (ADME). Lipophilicity influences membrane permeability, while solubility affects bioavailability; both are vital for effective drug absorption and distribution. Pharmacokinetic properties and drug-likeness, which are shaped by factors like molecular weight and hydrogen bonding, are significant indicators of a compound's potential for clinical success. Indole derivatives demonstrate a broad spectrum of pharmacological activities, including anti-inflammatory and antimicrobial properties, highlighting the need for careful optimization of these characteristics to enhance their therapeutic effectiveness. In this study, a series of 3-substituted indole derivatives were synthesized and systematically characterized, including positional isomers with -NO₂ as well as substitutions like Br, hydroxy and phenyl groups. We conducted density functional theory (DFT) calculations on the synthesized indole derivatives at the B3LYP/6-311G(d,p) level using the G16W software package to investigate their thermochemical properties, physicochemical attributes, frontier molecular orbitals (FMOs) and molecular electrostatic potential (MEP) plots also estimated lipophilicity and water solubility to evaluate their dissolution behavior in octanol and water. Pharmacokinetic properties and drug-likeness profiles were further evaluated using in silico prediction tools. Moreover, a comprehensive molecular docking study was conducted on five rationally designed derivatives against the kinase domain of VEGFR2 to examine their potential binding interactions and therapeutic relevance. Overall, this study provides valuable molecular-level insights into how structural modifications influence physicochemical and biological properties, thereby offering strategic guidance for the rational design and development of indole-based drug candidates.