Synthesis of Sulfadiazinyl acyl/aryl thiourea derivatives as calf intestinal alkaline phosphatase inhibitors, Pharmacokinetic properties, Lead optimization, Lineweaver-Burk plot evaluation and Binding analysis

Publication date: Available online 2 June 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Sajid-ur-Rehman, Aamer Saeed, Gufran Saddique, Pervaiz Ali Channar, Fayaz Ali Larik, Qamar Abbas, Mubashir Hassan, Hussain Raza, Tanzeela Abdul Fattah, Sung-Yum Seo
To seek the new medicinal potential of sulfadiazine drug, the free amino group of sulfadiazine was exploited to obtain acyl/aryl thioureas using simple and straightforward protocol. Acyl/aryl thioureas are well recognized bioactive pharmacophore containing moieties. A new series (4a-4j) of sulfadiazine derived acyl/aryl thioureas was synthesized and characterized through spectroscopic and elemental analysis. The synthesized derivatives 4a-4j were subjected to calf intestinal alkaline phosphatase (CIAP) activity. The derivative 4a-4j showed better inhibition potential compared to standard monopotassium phosphate (MKP). The compound 4c exhibited higher potential in the series with IC50 0.251±0.012µM (standard KH2PO4 4.317±0.201µM). Lineweaver-Burk plots revealed that most potent derivative 4c inhibition CIAP via mixed type pathway. Pharmacological investigations showed that synthesized compounds 4a-4j obey Lipinsk's rule. ADMET parameters evaluation predicted that these molecule show significant lead like properties with minimum possible toxicity and can serve as templates in drug designing. The synthetic compounds show none mutagenic and irritant behavior. Molecular docking analysis showed that compound 4c interacts with Asp273, His317 and Arg166 amino acid residues.

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