Synthesis of novel hydrazide Schiff bases with anti-diabetic and anti-hyperlipidemic effects: in-vitro, in-vivo and in-silico approaches

Abstract

The increasing global incidence of non-insulin-dependent diabetes mellitus (NIDDM) necessitates innovative therapeutic solutions. This study focuses on the design, synthesis and biological evaluation of Schiff base derivatives from 2-bromo-2-(2-chlorophenyl) acetic acid, particularly hydrazone compounds 4a and 4b. Both in-vitro and in-vivo assays demonstrate these derivatives’ strong antidiabetic and anti-hyperlipidemic properties. In a 15-d experiment, we administered 4a and 4b at doses of 2.5 and 5 mg/kg body weight, which effectively improved symptoms of alloxan-induced diabetes in mice. These symptoms included weight loss, increased water consumption and high blood glucose levels. The compounds also normalized abnormal levels of total cholesterol (TC), triacylglycerol (TG) and low-density lipoprotein cholesterol (LDL-C), while raising the levels of high-density lipoprotein cholesterol (HDLC). Computational analysis showed that these compounds effectively inhibited the α-glucosidase enzyme by interacting with key catalytic residues, specifically Asp214 and Asp349. These computational results were confirmed through in-vitro tests, where 4a and 4b showed strong α-glucosidase inhibitory activity, with IC₅₀ values of 0.70 ± 0.11 and 10.29 ± 0.30 µM, respectively. These compounds were more effective than the standard drug, acarbose, which had an IC₅₀ value of 873.34 ± 1.67 µM. Mechanistic studies further indicated competitive inhibition, reinforcing the therapeutic potential of 4a and 4b for NIDDM treatment.

Communicated by Ramaswamy H. Sarma

Keywords:

• Diabetes mellitus
• 2-bromo-2-(2-chlorophenyl) acetic acid
• schiff base
• α-glucosidase
• in-vivo studies
• molecular docking

Acknowledgments

The project was supported by grant from the Oman Research Council (TRC) through the funded project (BFP/RGP/HSS/23/037). The authors extend their appreciation to the Deputyship for Research and Innovation, Ministry of Education in Saudi Arabia for funding this research work through the project with number: ISP23-81.

Availability of data and materials

Anything related to this article can be obtained from the corresponding authors.

Ethics approval and consent to participate

The experimental procedures on animals were approved by the Institutional Ethical Committee of (DAEC/PHARM/2016/15) University of Swabi, KPK, Pakistan and were carried out in compliance with the 1986 UK Animal Scientific Procedure Act.

Consent for publication

Not relevant.

Disclosure statement

The authors declare that they have no conflict of interest.

Additional information

Funding

The authors extend their appreciation to the Deputyship for Research and Innovation, Ministry of Education in Saudi Arabia for funding this research work through the project with number: ISP23-81. The project was supported by grant from The Oman Research Council (TRC) through the funded project (BFP/RGP/HSS/23/037).