Ionic liquid [FcMeBIMIoct] [Br−] catalyzed multicomponent synthesis, anticancer activity, in silico ADMET, DFT, QSAR and molecular docking studies of new dihydropyrimidine-thiones

Abstract

The present investigation deals with the ionic liquid [FcMeBIMIoct][Br⁻] catalyzed multicomponent synthesis of a new series of multi-functionalized dihydropyrimidinethiones (8a-k) under microwave irradiation. [FcMeBIMIoct] [Br⁻] was found to be an efficient catalyst and afforded high yields in shorter reaction times. The synthesized compounds were screened for in vitro anticancer activity against three human cancer cell lines viz. breast (MCF-7), liver (HepG2), and lung (A549). 8j was found to be the most active compound, with an IC₅₀ value of 0.12 µM against the MCF-7 cell line. Moreover, compound 8b exerted significantly higher anticancer activity, with an IC₅₀ value of 0.11 µM against both the hepatic cancer cell line (HepG2) and lung cancer cell line (A549), compared to the standard drug 5-fluorouracil (IC₅₀ = 0.21 and 0.17 µM respectively). Furthermore, in silico ADMET, bioactivity prediction and QSAR studies revealed that dihydropyrimidinethiones exhibited a good pharmacological profile and strong interactions with target receptors. Molecular docking analysis predicted that compounds 8b and 8k demonstrated significant binding affinity with the Eg5 kinesin receptor, with the lowest binding energy of −8.4 kcal/mole followed by 8i and 8e, among binding energies −8.7 and −9.3 kcal/mole respectively. The active compounds were stabilized by hydrogen bonds, electrostatic interactions, pi-alkyl and pi-ally interactions which were additionally assisted by evaluation of HOMO-LUMO energies, electron affinity, diploe moment, and ionization potential, etc. using DFT analysis. The present research focuses on the medicinal noteworthiness of the target compounds as potential anticancer agents.