Novel N-6-X-3-pyridinoyl-N'-4-chlorophenylthioureas (X = Cl, Me): Synthesis, characterization, computational analysis and in silico biological activity studies
Karzan Mahmood Ahmed, Rahman Azeez Muhammed, Rebaz Anwar Omer, Yousif Hussein Azeez, Rebaz Obaıd Kareem, Rzgar Faruq Rashid, Elizaveta V. Panova, Damir A. Safin
Abstract
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.