Putting forward novel sulfonamide-thiazole-pyrazoline hybrids as potential central core structure for the development of non-specific b-TNAP and c-IAP inhibitors

Alkaline phosphatases (ALPs) play crucial role in various functions of human body, such as bone formation, metabolism in liver and intestines, and transfer of nutrients from mother to fetus during pregnancy. However, their overexpression is associated with severe consequences in different patients, such as deposition of minerals in dialysis patients also called coronary calcification and increased bone turnover in patients facing cancer metastization. Due to their involvement in crucial functions of human body and association with such harsh consequences, there is need of newer efficient ALP inhibitors that can tackle ALP excess without derailing the progress of normal functions. In this study, we reported synthesis and biological evaluation of novel series of sulfonamide-thiazole-pyrazoline hybrids (8a-j). The substitutions on the terminal phenyl groups of pyrazoline ring were designed as the basis for the SAR; however, all compounds showed efficient ALP (b-TNAP and c-IAP) inhibition activity, with 8c (IC₅₀ = 0.87±0.11 μM) being the most potent against b-TNAP and 8f (IC₅₀ = 2.11±0.34 μM) being the most potent against c-IAP. In addition, in silico studies were also conducted to provide insights into the binding interactions, drug-likeness and charge density of structures. The IC₅₀ results for all of the compounds were better compared to both references irrespective of the substitutions attached, therefore the sulphonamide-thiazole-pyrazoline hybrid core can be put forward as the central core for designing new drugs for non-specific ALP inhibition.