Synthesis of new pyrazine-thiazole analogs: Molecular modeling, anticancer activity, and pharmacokinetic properties

A series of pyrazine-linked thiazoles through amino-benzylidene bridges (3, 4, 6, 8, 9, and 11) were synthesized, and their structures were confirmed through infrared (IR), nuclear magnetic resonance (NMR), and mass spectrometry (MS) analyses. The preparation strategy was built on the interaction between the thiosemicarbazone derived from 2-(4-acetylphenyl)amino-pyrazine (1) and several halo-carbonyl reagents. The density functional theory (DFT) studies of representative examples of the synthesized conjugates 4c, 6c, and 11c revealed that they have non-planar configurations and different electronic properties, such as frontier molecular orbitals (FMOs) energies, polarizability, and hyperpolarizability. Moreover, the cytotoxic effectiveness of the synthesized pyrazine-thiazole analogs was appraised towards three tumor cell lines (Panc-1, HepG2, and MCF-7) and a normal cell line (WI-38), where it revealed good anti-tumor activity, likened to the standard drug erlotinib. Analog 6c had a comparable inhibitory activity towards all tumor cell lines, especially against MCF-7 (IC50 = 5.51±0.09 μM), while analog 9 had significant cytotoxicity against Panc-1. Also, analog 11c had strong activity, especially against HepG2 (IC50 = 8.01±0.35 μM). Moreover, the hybrids’ ability to constrain human carbonic anhydrase isoforms was evaluated and exhibited strong inhibitory effects, comparable to acetazolamide (AZA), especially against Zinc containing metalloprotein catalyzes the reversible hydration of carbon dioxide (CAIX). The analog 3, which contains a thiazol-4-one moiety, displayed preferential efficiency against CAXII over CAIX, whereas hybrid 4c had uniform inhibition toward both isoforms (IC50 = 0.052 ± 0.014 and 0.091 ± 0.018 μM, respectively). Further, the molecular dockage performance of the synthesized derivatives was conducted towards the 6CB0 amino acid to evaluate their binding affinities, interactions, and potential efficacy. Analogs 4b and 6b demonstrated high binding affinities along with multiple stabilizing interactions. Additionally, the pharmacokinetic properties of produced conjugates were explored using SwissADME. Hybrids 2, 3, and 4a-c exhibited high GI absorption and moderate solubility. Conversely, certain analogs like 11a-c displayed low solubility and absorption. Finally, hybrid 6c exhibited strong anti-cancer activity against MCF-7 and noteworthy CA isoform inhibition comparable to AZA. Molecular docking studies revealed high binding affinities and pharmacokinetic analysis suggested fortunate absorption for some hybrids.