Development of novel cyclopropyl tethered iminothiazolidinone-isatin hybrids as effective multi target intestinal alkaline phosphatase, urease and α-glucosidase inhibitors.

In the pursuit of potent enzyme inhibitors to combat metabolic and microbial diseases, here we report the rational design and synthesis of novel cyclopropyl-tethered 2-iminothiazolidin-4-one-isatin hybrids (7a-k), aimed at overcoming limitations of current therapeutics in terms of potency, selectivity, and safety. The structures were confirmed through spectroscopy and compounds were assessed for inhibitory potential against α-glucosidase, urease, and Intestinal Alkaline phosphatase (IALP). Notably, compound (7d) featuring n-heptyl chain exhibited the highest potency against IALP, with an IC₅₀ value of 55.70 ± 0.19 μM "mean ± SEM (n = 2)", surpassing the standard L-phenylalanine (IC₅₀ = 80.7 ± 0.09 μM). For urease inhibition, n-butyl substituted compound (7a) demonstrated the highest effectiveness (IC₅₀ = 56.52 ± 0.14 μM), while n-pentyl substituted compound (7b) showed the pronounced α-glucosidase inhibition (IC₅₀ = 63.80 ± 0.15 μM) however less active than their standard inhibitors. The SAR analysis indicated that variations in aryl and alkyl substituents, particularly alkyl chain length, significantly influenced biological activity. Interestingly compounds (7j) and (7k) were found to be the least active for all enzymes. Computational studies provided further insights into the compounds' electronic properties, binding affinities, and pharmacokinetic profiles. All these findings underscore the therapeutic potential of cyclopropyl-tethered 2-iminothiazolidin-4-one-isatin hybrids as a promising scaffold for multifunctional enzyme inhibition, paving the way for future drug discovery and optimization efforts.