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Bi-heterocyclic benzamides as alkaline phosphatase inhibitors: Mechanistic comprehensions through kinetics and computational approaches.
Arch Pharm (Weinheim). 2019 Mar; 352(3):e1800278.AP

Abstract

Novel bi-heterocyclic benzamides were synthesized by sequentially converting 4-(1H-indol-3-yl)butanoic acid (1) into ethyl 4-(1H-indol-3-yl)butanoate (2), 4-(1H-indol-3-yl)butanohydrazide (3), and a nucleophilic 5-[3-(1H-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 of 4 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 compound 8b inhibited alkaline phosphatase non-competitively to form an enzyme-inhibitor complex. The inhibition constant Ki 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.

Authors+Show Affiliations

Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju, South Korea. Department of Chemistry, Government College University, Lahore, Pakistan.Department of Chemistry, Government College University, Lahore, Pakistan.Department of Chemistry, Government College University, Lahore, Pakistan.Department of Chemistry, Government College University, Lahore, Pakistan.Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju, South Korea.Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju, South Korea.Faculty of Pharmacy and Atta-ur-Rahman Institute for Natural Products Discovery (AuRIns), Level 9, FF3, Universiti Teknologi MARA, Puncak Alam Campus, Selangor Darul Ehsan, Malaysia.Department of Biochemistry, University of Agriculture, Faisalabad, Pakistan.Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju, South Korea.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30624805

Citation

Abbasi, Muhammad A., et al. "Bi-heterocyclic Benzamides as Alkaline Phosphatase Inhibitors: Mechanistic Comprehensions Through Kinetics and Computational Approaches." Archiv Der Pharmazie, vol. 352, no. 3, 2019, pp. e1800278.
Abbasi MA, Nazir M, Ur-Rehman A, et al. Bi-heterocyclic benzamides as alkaline phosphatase inhibitors: Mechanistic comprehensions through kinetics and computational approaches. Arch Pharm (Weinheim). 2019;352(3):e1800278.
Abbasi, M. A., Nazir, M., Ur-Rehman, A., Siddiqui, S. Z., Hassan, M., Raza, H., Shah, S. A. A., Shahid, M., & Seo, S. Y. (2019). Bi-heterocyclic benzamides as alkaline phosphatase inhibitors: Mechanistic comprehensions through kinetics and computational approaches. Archiv Der Pharmazie, 352(3), e1800278. https://doi.org/10.1002/ardp.201800278
Abbasi MA, et al. Bi-heterocyclic Benzamides as Alkaline Phosphatase Inhibitors: Mechanistic Comprehensions Through Kinetics and Computational Approaches. Arch Pharm (Weinheim). 2019;352(3):e1800278. PubMed PMID: 30624805.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Bi-heterocyclic benzamides as alkaline phosphatase inhibitors: Mechanistic comprehensions through kinetics and computational approaches. AU - Abbasi,Muhammad A, AU - Nazir,Majid, AU - Ur-Rehman,Aziz, AU - Siddiqui,Sabahat Z, AU - Hassan,Mubashir, AU - Raza,Hussain, AU - Shah,Syed A A, AU - Shahid,Muhammad, AU - Seo,Sung-Yum, Y1 - 2019/01/09/ PY - 2018/09/20/received PY - 2018/11/29/revised PY - 2018/12/05/accepted PY - 2019/1/10/pubmed PY - 2019/6/14/medline PY - 2019/1/10/entrez KW - benzamides KW - bi-heterocyclic KW - kinetics KW - molecular docking KW - phosphatase SP - e1800278 EP - e1800278 JF - Archiv der Pharmazie JO - Arch. Pharm. (Weinheim) VL - 352 IS - 3 N2 - Novel bi-heterocyclic benzamides were synthesized by sequentially converting 4-(1H-indol-3-yl)butanoic acid (1) into ethyl 4-(1H-indol-3-yl)butanoate (2), 4-(1H-indol-3-yl)butanohydrazide (3), and a nucleophilic 5-[3-(1H-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 of 4 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 compound 8b inhibited alkaline phosphatase non-competitively to form an enzyme-inhibitor complex. The inhibition constant Ki 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. SN - 1521-4184 UR - https://www.unboundmedicine.com/medline/citation/30624805/Bi_heterocyclic_benzamides_as_alkaline_phosphatase_inhibitors:_Mechanistic_comprehensions_through_kinetics_and_computational_approaches_ L2 - https://doi.org/10.1002/ardp.201800278 DB - PRIME DP - Unbound Medicine ER -