Quantum chemical modeling, molecular docking, and ADMET evaluation of imidazole phenothiazine hybrids

Cancer is one of the biggest challenges for health concerns in the world. There are so many drugs available, but they have a lack of specificity, poor safety, side effects, and the development of resistance. Therefore, there is an urgent need for much safer and more targeted anticancer treatments. Nitrogen-containing heterocycles play an important role in the development of drugs. Recently, imidazole and phenothiazine rings are well known for their antiproliferative and anticancer activities. This study employs the molecular hybridisation method to link these bioactive scaffolds and develop novel N-substituted imidazole-phenothiazine (N-IPTZ) hybrids. All the synthesised hybrids were characterised by using analytical techniques such as ¹H-NMR,¹³C-NMR, mass spectrum, and FT-IR. Furthermore, the DFT analysis under the B3LYP/6-311G(d, p) level in gas phase to optimise and correlate the structures of the synthesised hybrids was also performed. The optimised structure was used to determine the energies of frontier molecular orbitals (HOMO-LUMO), quantum chemical descriptors (QCD), and molecular electrostatic potentials (MEP). Additionally, in silico approaches such as ADMET, BOILED-Egg, and bioactivity radar were also performed to evaluate the oral bioavailability of the synthesised hybrids. Molecular docking and MD simulation studies were also conducted to assess the interaction profile of the synthesised hybrids with cancer target receptors like EGFR, IGF, VEGFR1, VEGFR2, and PARP-2. It was found through docking studies that the synthesised N-IPTZ(a-c) hybrids might interact with amino acids such as GLY695, SER696, GLY697, ALA698, PHE699, LYS721, GLY772, CYS773, THR766, GLN767, LEU768, MET769, ARG817, ASN818, and THR830. Additionally, it reveals hydrogen bonding with ASP831, with binding energies of - 7.23, - 6.11, and - 5.93 kcal/mol. Moreover, all the synthesised hybrids were also analysed for their anti-cancer activity against the human liver cancer cell line (HepG2) by MTT assay. Obtained results revealed that N-IPTZ(c) exhibited anticancer activity with an IC₅₀ value of 35.3 µg/mL.