Synthesis, Molecular Docking, and Preclinical Evaluation of a New Succinimide Derivative for Cardioprotective, Hepatoprotective and Lipid-Lowering Effects

Abstract

Cardiac and hepatotoxicities are major concerns in the development of new drugs. Better alternatives to other treatments are being sought to protect these vital organs from the toxicities of these pharmaceuticals. In this regard, a preclinical study is designed to investigate the histopathological effects of a new succinimide derivative (Comp-1) on myocardial and liver tissues, and the biochemical effects on selected cardiac biomarkers, hepatic enzymes, and lipid profiles. For this, an initially lethal/toxic dose was determined, followed by a grouping of selected albino rats into five groups (each group had n = 6). The control group received daily oral saline for 8 days. The 5-FU (5-Fluorouracil) group received oral saline daily for 8 days, added with the administration of a single dose of 5-FU (150 mg/kg I.P.) on day 5 of the study. The atenolol group received oral atenolol (20 mg/kg) for 8 days and 5-FU (150 mg/kg I.P.) on day 5 of the protocol. Similarly, two groups of rats treated with test compound (Comp-1) were administered with 5 mg/kg I.P. and 10 mg/kg I.P. for 8 days, followed by 5-FU (150 mg/kg I.P.) on day 5. Toxicity induced by 5-FU was manifested by increases in the serum creatinine kinase myocardial band (CK-MB), troponin I (cTnI) and lactate dehydrogenase (LDH), lipid profile, and selected liver enzymes, including ALP (alkaline phosphatase), ALT (alanine transaminase), AST (aspartate aminotransferase), BT (bilirubin total), and BD (direct bilirubin). These biomarkers were highly significantly decreased after the administration of the mentioned doses of the test compound (5 mg/kg and 10 mg/kg). Similarly, histological examination revealed cardiac and hepatic tissue toxicity by 5-FU. However, those toxic effects were also significantly recovered/improved after the administration of Comp-1 at the said doses. This derivative showed dose-dependent effects and was most effective at a dose of 10 mg/kg body weight. Binding energy data computed via docking simulations revealed that our compound interacts toward the human beta2-adrenergic G protein-coupled receptor (S = −7.89 kcal/mol) with a slight stronger affinity than the calcium channel T-type (S = −7.07 kcal/mol). In conclusion, the histological and biochemical results showed that the test compound (Comp-1) had prominent cardioprotective, hepatoprotective, and lipolytic effects against 5-FU-induced toxicity in the subjected animal model.

New Succinimide–Thiazolidinedione Hybrids as Multitarget Antidiabetic Agents: Design, Synthesis, Bioevaluation, and Molecular Modelling Studies

“…Similarly, previously, pyrrolidinedione has also been reported to possess a strong antidiabetic effect [ 38 , 39 ]. Moreover, chiral succinimides have already been reported to have a number of potential cardio and hepatoprotective activities [ 40 ]. Chiral compounds with absolute stereo purity have also been reported recently with a strong antidiabetic activity [ 41 ].…”

Exploration of Succinimide Derivative as a Multi-Target, Anti-Diabetic Agent: In Vitro and In Vivo Approaches

“…A properly designed agent, which could be effective on many targets, makes an advantageous and effective multi-targeted agent. This study was thoughtfully planned to investigate the efficacy of a succinimide derivative as a multi-target anti-diabetic drug [ 60 , 61 ]. The synthetic substance effectively inhibited the enzymes α-glucosidase, α-amylase, and protein tyrosine phosphatase 1 B [ 62 , 63 ].…”

Modification of 4-(4-chlorothiophen-2-yl)thiazol-2-amine derivatives for the treatment of analgesia and inflammation: synthesis and in vitro, in vivo, and in silico studies

“…Various synthetic reactions provide baseline structural units for pharmacologically important molecules. Previously, we reported the synthetic approaches for the synthesis of various medicinally important compounds ( Bibi et al, 2020 ; Qayyum et al, 2022 ). The medicinal compounds, particularly the nitrogenous moieties, have been explored for various medicinal purposes ( Nugent et al, 2012 ; Sadiq et al, 2015 ; Sadiq and Nugent, 2020 ; Sadiq et al, 2022 ).…”