Novel N-6-X-3-pyridinoyl-N'-4-chlorophenylthioureas (X = Cl, Me): Synthesis, characterization, computational analysis and in silico biological activity studies

• We report new thiourea derivatives N -6-X-3-pyridinoyl- N' −4-chlorophenylthiourea ( X = Cl, 1 ; Me, 2 ). • 1 and 2 were characterized by the means of elemental analysis data, IR and 1 H NMR spectroscopy. • The formation of two conformers were revealed for 2 in DMSO . • 1 and 2 were studied using the DFT/B3LYP/6–311++G(d,p)-based calculations. • Molecular docking revealed positive activity of 1 and 2 toward hemoglobin S. In this work, to develop novel agents capable of inhibiting hemoglobin S (HbS), which is the primary cause of sickle cell anemia (SCA), we synthesized two new phenyl-pyridinoyl-thiourea derivatives namely N -6‑chloro-3-pyridinoyl- N' -4-chlorophenylthiourea ( 1 ) and N -6-methyl-3-pyridinoyl- N' -4-chlorophenylthiourea ( 2 ). Compounds 1 and 2 were obtained through a one-pot reaction of 6-chloronicotinoyl chloride with an equimolar amount of KSCN followed by the addition of an equimolar amount of 4-chloroaniline or 4-aminotoluene, respectively, in the medium of acetone. The formation of both compounds was proved by the means of elemental analysis data, IR and 1 H NMR spectroscopy. Notably, the 1 H NMR spectrum of 2 recorded in DMSO‑ d 6 revealed two sets of signals corresponding to two isomers, while the same spectrum of 1 exhibited only one set of signals. Both isomeric forms of 1 and 2 were studied using the DFT-based calculations, which allowed to conclude that the formation of two isomeric forms of 2 is energetically more favorable in the DMSO medium in comparison to 1 . The biological activities of the discussed compounds were analyzed in silico to reveal their potential ADMET properties. It was predicted that both 1 and 2 belong to the fifth class of toxicity and are hepato-, neuro-, eco- and nutritionally toxic, while they are inactive in nephro-, cardio-, immuno-, cyto-, respiratory and clinical toxicity, and in carcinogenicity and mutagenicity. As evidenced from the molecular docking simulations, both 1 and 2 exhibit a potential activity to inhibit HbS, with the corresponding ligand efficiency scores being well within the range for a Hit.