Coumarin tethered cyclic imides as efficacious glucose uptake agents and investigation of hit candidate to probe its binding mechanism with human serum albumin

• Published in: Bioorganic chemistry Vol. 92; p. 103212
• Main Authors: Reddy, Dinesh S., Kongot, Manasa, Singh, Vishal, Maurya, Neha, Patel, Rajan, Kumar Singhal, Nitin, Avecilla, Fernando, Kumar, Amit
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.11.2019; Elsevier
• Subjects: Biochemistry & Molecular Biology; Chemistry; Chemistry, Organic; Coumarins; Cyclic imides; Glucose uptake; Human serum albumin (HSA); Life Sciences & Biomedicine; Physical Sciences; Science & Technology; Solution stability studies; Coumarins; Solution stability studies; Glucose uptake; Human serum albumin (HSA); Cyclic imides; DNA CLEAVAGE; PK(A) VALUES; PYRIMIDINE HYBRIDS; ALPHA-GLUCOSIDASE; COMPLEXES; DPP-4 INHIBITOR; POTENT ANTICANCER; BIOLOGICAL EVALUATION; DERIVATIVES; CYTOTOXICITY
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.103212

[Display omitted] •Coumarin-cyclic imide conjugates were designed for glucose uptake activity.•Compound 1f identified as hit candidate exhibited 85.21% of glucose uptake.•All the compounds displayed good safety profile in HEK293 cell lines.•Active compounds were stable at varied pH conditions.•Compound 1f binds with HSA without disrupting its secondary structure. A series of novel coumarin-cyclic imide conjugates (1a–1j) were designed and synthesized to evaluate their glucose uptake activity by insulin resistant liver hepatocyte carcinoma (HepG2) cells through 2-NBDG uptake assay. Compounds (1a–1j) were characterised using various analytical methods such as 1H NMR, 13C NMR, IR, GC–MS, elemental and single-crystal X-ray diffraction techniques. Compounds (1a–1j) exhibited 85.21 – 65.80% of glucose uptake and showed low level of cytotoxicity towards human embryonic kidney cells (HEK-293) indicating good selectivity and safety profile. Compound 1f was identified as a hit candidate exhibiting 85.21% of glucose uptake which was comparable with standard antidiabetic drug Metformin (93.25% glucose uptake). Solution stability study under physiological pH conditions ≈ (3.4 – 8.7), indicates that compound 1f is sufficiently stable at varied pH conditions and thereby compatible with bio-physiological environments. Interaction of 1f with human serum albumin (HSA) were also studied which quantifies that compound 1f binds with HSA efficiently through facile binding reaction in solution. Fluorescence, UV–vis spectrophotometry and molecular modeling methodologies were employed for studying the interaction mechanism of compound 1f with protein.