Computational and experimental investigations of novel 1,3-disubstituted thioureas as the dual inhibitor of b-TNAP and b-CAII enzyme for Cancer treatment.

The various chemical properties and potential biological activities of thiourea and its derivatives, particularly as anticancer agents, has sparked interest in the field of medicinal chemistry. This research is focused on the synthesis of new, 1,3-disubstituted derivatives of thiourea (14-20), by the reaction of substituted anilines with the substituted benzoyl thiocyanate. This synthetic strategy was an innovative approach that effectively allowed for the generation of a diverse thiourea derivatives. The structures of the synthesized compounds were confirmed by using spectroscopic methods such as FTIR and NMR ([1]H and 13C) confirming the effective synthesis of the targeted compounds. Each of the compounds that were synthesized underwent biological activity testing against two different enzymes i.e., tissue- non-specific alkaline phosphatases (b-TNAP) and carbonic anhydrases II (b-CA-II), which are both important enzymes that promote the progression of various cancers. In the in-vitro test, all the compounds demonstrated the anticancer potential of dual enzyme inhibition. The standard in vitro spectrophotometric enzyme assays confirmed the enzyme inhibition. Of all the compounds, compound 15 exhibited notable dual inhibition with an IC50 of 0.69 ± 0.05 μM and 1.25 ± 0.03 μM, respectively. The derivative exhibited roughly 20 to 25 times more inhibition compared to the standards used, levamisole and acetazolamide, which were selected due to their known inhibitory effects against b-TNAP and b-CA-II, respectively. The results were further supported by molecular docking studies, which highlighted the ability of the synthesized compounds to interact with the active site of the targeted enzymes b-TNAP and b-CA-II. Furthermore, the synthesized compounds obtained positive results from ADMET predictions confirming their accrued pharmacokinetic profiles and drug-likeness properties. This suggests the synthesized compounds can be considered potential lead compounds to synthesize more potential compounds for the treatment of cancer and its associated malignancies.