Synthesis, molecular modelling, and biological evaluation of new pyrazine-oxadiazole hybrids as anticancer agents
Abstract
Three various pyrazine-oxadiazole hybrids 4a-c , 7a-c , and 10a-c were synthesized by reacting the precursor, 4-(pyrazin-2-ylamino)benzohydrazide ( 2 ), with different substituted benzoic acids, aryl isothiocyanates, where the produced thiosemicarbazides cyclized with iodine/NaOH, or aromatic aldehydes, followed by heating the produced hydrazones with acetic anhydride. The scrutinized compounds exhibited analogous planar optimized structures, except for the methoxyphenyl hybrids 4b and 7b, along with the acetyl derivatives 10a-c, which deviated from planarity. The frontier molecular orbitals (FMO) plots of analogues 4a-c and 7a-c revealed a comparable distribution of their highest occupied molecular orbital (HOMO), whereas their Lowest unoccupied molecular orbital (LOMO)s have an alternative structure. As well, from the in vitro anti-tumor activity against three human cancer cells, hybrid 10b displayed a significant activity against HT-29 and Michigan cancer foundation-7 (MCF-7, breast cancer cell line) cells (IC 50 = 15.26±0.28 and 14.62±0.20 µM, respectively). However, hybrid 7b showed superior effectiveness towards MCF-7 cells (IC 50 = 22.57±0.48 µM). Besides, the synthesized hybrids were evaluated for their binding affinity with the human topoisomerase (PDB: 4OLE). Hybrids 7a , 7c , and 10a demonstrated high binding scores (S = -6.6199, -6.2440, and -6.0356 kcal/mol), respectively. Finally, the estimated pharmacokinetic profiles using the Swiss absorption, distribution, metabolism and excretion (ADME) online program were performed and showed that hybrids 7c and 10c exhibited enhanced polar surface areas but reduced their blood–brain barrier (BBB) permeability, emphasizing the balance between hydrophilicity and lipophilicity through the drug’s construction. These discoveries establish the hybrids’ potential as an anticancer drug while providing insights into their physicochemical and ADME profiles.