Bi‐heterocyclic benzamides as alkaline phosphatase inhibitors: Mechanistic comprehensions through kinetics and computational approaches. Issue 3 (9th January 2019)

• Record Type: Journal Article
• Authors: Abbasi, Muhammad A.; Nazir, Majid; ur‐Rehman, Aziz; Siddiqui, Sabahat Z.; Hassan, Mubashir; Raza, Hussain; Shah, Syed A. A.; Shahid, Muhammad; Seo, Sung‐Yum
• Is Part Of: Archiv der Pharmazie. Volume 352:Issue 3(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-01-09
• Subjects: benzamides -- bi‐heterocyclic -- kinetics -- molecular docking -- phosphatase; Pharmaceutical chemistry -- Periodicals; Pharmacology -- Periodicals; 615.19
• DOI: 10.1002/ardp.201800278
• Languages: English
• ISSNs: 0365-6233

Abstract

Abstract: Novel bi‐heterocyclic benzamides were synthesized by sequentially converting 4‐(1 H ‐indol‐3‐yl)butanoic acid (1 ) into ethyl 4‐(1 H ‐indol‐3‐yl)butanoate (2 ), 4‐(1 H ‐indol‐3‐yl)butanohydrazide (3 ), and a nucleophilic 5‐[3‐(1 H ‐indol‐3‐yl)propyl]‐1, 3, 4‐oxadiazole‐2‐thiol (4 ). In a parallel series of reactions, various electrophiles were synthesized by reacting substituted anilines (5a–k ) with 4‐(chloromethyl)benzoylchloride (6 ) to afford 4‐(chloromethyl)‐ N ‐(substituted‐phenyl)benzamides (7a–k ). Finally, the nucleophilic substitution reaction of4 was carried out with newly synthesized electrophiles, 7a–k, to acquire the targeted bi‐heterocyclic benzamides, 8a–k . The structural confirmation of all the synthesized compounds was done by IR, 1 H NMR, 13 C NMR, EI‐MS, and CHN analysis data. The inhibitory effects of these bi‐heterocyclic benzamides (8a–k ) were evaluated against alkaline phosphatase, and all these molecules were identified as potent inhibitors relative to the standard used. The kinetics mechanism was ascribed by evaluating the Lineweaver–Burk plots, which revealed that compound8b inhibited alkaline phosphatase non‐competitively to form an enzyme–inhibitor complex. The inhibition constant K i calculated from Dixon plots for this compound was 1.15 μM. The computational study was in full agreement with the experimental records and these ligands exhibited good binding energy values. These molecules also exhibited mild cytotoxicity toward red blood cell membranes when analyzed through hemolysis. So, these molecules might be deliberated as nontoxic medicinal scaffolds to render normal calcification of bones and teeth. Abstract : Novel bi‐heterocyclic benzamides8a–k were synthesized and assayed for their inhibitory effects on alkaline phosphatase. All these molecules were identified as potent inhibitors relative to the standard used. Compound8b inhibits alkaline phosphatase non‐competitively forming an enzyme–inhibitor complex. The computational study revealed these ligands to exhibit good binding energy values.