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Synthesis and structure-activity relationship of tyrosinase inhibiting novel bi-heterocyclic acetamides: Mechanistic insights through enzyme inhibition, kinetics and computational studies.
Bioorg Chem. 2019 05; 86:459-472.BC

Abstract

The present research was designed for the selective synthesis of novel bi-heterocyclic acetamides, 9a-n, and their tyrosinase inhibition to overwhelm the problem of melanogenesis. The structures of newly synthesized compounds were confirmed by spectral techniques such as 1H NMR, 13C NMR, and EI-MS along with elemental analysis. The inhibitory effects of these bi-heterocyclic acetamides (9a-n) were evaluated against tyrosinase and all these molecules were recognized as potent inhibitors relative to the standard used. The Kinetics mechanism was analyzed by Lineweaver-Burk plots which explored that compound, 9h, inhibited tyrosinase competitively by forming an enzyme-inhibitor complex. The inhibition constants Ki calculated from Dixon plots for this compound was 0.0027 µM. The computational study was coherent with the experimental records and these ligands exhibited good binding energy values (kcal/mol). The hemolytic analysis revealed their mild cytotoxicity towards red blood cell membranes and hence, these molecules can be pondered as nontoxic medicinal scaffolds for skin pigmentation and related disorders.

Authors+Show Affiliations

Department of Chemistry, Government College University, Lahore 54000, Pakistan.Department of Chemistry, Government College University, Lahore 54000, Pakistan; College of Natural Sciences, Department of Biological Sciences, Kongju National University, Gongju 32588, South Korea. Electronic address: abbasi@gcu.edu.pk.Department of Chemistry, Government College University, Lahore 54000, Pakistan.Department of Chemistry, Government College University, Lahore 54000, Pakistan.College of Natural Sciences, Department of Biological Sciences, Kongju National University, Gongju 32588, South Korea.College of Natural Sciences, Department of Biological Sciences, Kongju National University, Gongju 32588, South Korea.Faculty of Pharmacy and Atta-ur-Rahman Institute for Natural Products Discovery (AuRIns), Level 9, FF3, Universiti Teknologi MARA, Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia.Department of Biochemistry, University of Agriculture, Faisalabad 38040, Pakistan.College of Natural Sciences, Department of Biological Sciences, Kongju National University, Gongju 32588, South Korea. Electronic address: dnalove@kongju.ac.kr.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30772647

Citation

Butt, Abdul Rehman Sadiq, et al. "Synthesis and Structure-activity Relationship of Tyrosinase Inhibiting Novel Bi-heterocyclic Acetamides: Mechanistic Insights Through Enzyme Inhibition, Kinetics and Computational Studies." Bioorganic Chemistry, vol. 86, 2019, pp. 459-472.
Butt ARS, Abbasi MA, Aziz-Ur-Rehman , et al. Synthesis and structure-activity relationship of tyrosinase inhibiting novel bi-heterocyclic acetamides: Mechanistic insights through enzyme inhibition, kinetics and computational studies. Bioorg Chem. 2019;86:459-472.
Butt, A. R. S., Abbasi, M. A., Aziz-Ur-Rehman, ., Siddiqui, S. Z., Raza, H., Hassan, M., Shah, S. A. A., Shahid, M., & Seo, S. Y. (2019). Synthesis and structure-activity relationship of tyrosinase inhibiting novel bi-heterocyclic acetamides: Mechanistic insights through enzyme inhibition, kinetics and computational studies. Bioorganic Chemistry, 86, 459-472. https://doi.org/10.1016/j.bioorg.2019.01.036
Butt ARS, et al. Synthesis and Structure-activity Relationship of Tyrosinase Inhibiting Novel Bi-heterocyclic Acetamides: Mechanistic Insights Through Enzyme Inhibition, Kinetics and Computational Studies. Bioorg Chem. 2019;86:459-472. PubMed PMID: 30772647.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis and structure-activity relationship of tyrosinase inhibiting novel bi-heterocyclic acetamides: Mechanistic insights through enzyme inhibition, kinetics and computational studies. AU - Butt,Abdul Rehman Sadiq, AU - Abbasi,Muhammad Athar, AU - Aziz-Ur-Rehman,, AU - Siddiqui,Sabahat Zahra, AU - Raza,Hussain, AU - Hassan,Mubashir, AU - Shah,Syed Adnan Ali, AU - Shahid,Muhammad, AU - Seo,Sung-Yum, Y1 - 2019/01/26/ PY - 2018/09/19/received PY - 2019/01/07/revised PY - 2019/01/21/accepted PY - 2019/2/18/pubmed PY - 2020/4/14/medline PY - 2019/2/18/entrez KW - Acetamides KW - Binding energy KW - Hemolytic KW - Melanogenesis KW - Thiazole KW - Triazole KW - Tyrosinase SP - 459 EP - 472 JF - Bioorganic chemistry JO - Bioorg. Chem. VL - 86 N2 - The present research was designed for the selective synthesis of novel bi-heterocyclic acetamides, 9a-n, and their tyrosinase inhibition to overwhelm the problem of melanogenesis. The structures of newly synthesized compounds were confirmed by spectral techniques such as 1H NMR, 13C NMR, and EI-MS along with elemental analysis. The inhibitory effects of these bi-heterocyclic acetamides (9a-n) were evaluated against tyrosinase and all these molecules were recognized as potent inhibitors relative to the standard used. The Kinetics mechanism was analyzed by Lineweaver-Burk plots which explored that compound, 9h, inhibited tyrosinase competitively by forming an enzyme-inhibitor complex. The inhibition constants Ki calculated from Dixon plots for this compound was 0.0027 µM. The computational study was coherent with the experimental records and these ligands exhibited good binding energy values (kcal/mol). The hemolytic analysis revealed their mild cytotoxicity towards red blood cell membranes and hence, these molecules can be pondered as nontoxic medicinal scaffolds for skin pigmentation and related disorders. SN - 1090-2120 UR - https://www.unboundmedicine.com/medline/citation/30772647/Synthesis_and_structure_activity_relationship_of_tyrosinase_inhibiting_novel_bi_heterocyclic_acetamides:_Mechanistic_insights_through_enzyme_inhibition_kinetics_and_computational_studies_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0045-2068(18)30957-X DB - PRIME DP - Unbound Medicine ER -