Development of diarylpentadienone analogues as alpha-glucosidase inhibitor: Synthesis, in vitro biological and in vivo toxicity evaluations, and molecular docking analysis

Highlights

• Compounds 1–18 are new and non-PAINS associated molecules.

• 18 displayed good α-glucosidase inhibition with IC₅₀ of 5.69 ± 0. 5 µM via competitive inhibition.

• 18 is non-toxic towards zebrafish in vivo model.

• 18 participates in swv several important interactions in the binding sites of α-glucosidase.

Abstract

A series of aminated- (1–9) and sulfonamide-containing diarylpentadienones (10–18) were synthesized, structurally characterized, and evaluated for their in vitro anti-diabetic potential on α-glucosidase and DPP-4 enzymes. It was found that all the new molecules were non-associated PAINS compounds. The sulfonamide-containing series (compounds 10–18) selectively inhibited α-glucosidase over DPP-4, in which compound 18 demonstrated the highest activity with an IC₅₀ value of 5.69 ± 0.5 µM through a competitive inhibition mechanism. Structure-activity relationship (SAR) studies concluded that the introduction of the trifluoromethylbenzene sulfonamide moiety was essential for the suppression of α-glucosidase. The most active compound 18, was then further tested for in vivo toxicities using the zebrafish animal model, with no toxic effects detected in the normal embryonic development, blood vessel formation, and apoptosis of zebrafish. Docking simulation studies were also carried out to better understand the binding interactions of compound 18 towards the homology modeled α -glucosidase and the human lysosomal α -glucosidase enzymes. The overall results suggest that the new sulfonamide-containing diarylpentadienones, compound 18, could be a promising candidate in the search for a new α-glucosidase inhibitor, and can serve as a basis for further studies involving hit-to-lead optimization, in vivo efficacy and safety assessment in an animal model and mechanism of action for the treatment of T2DM patients.

Introduction

Diabetes mellitus or diabetes has become an increasing problem worldwide, both in rich and poor countries. It is a chronic and progressive disease associated with elevated glucose levels in the blood and is known as hyperglycaemia if the condition persists over a prolonged period. Over time, diabetes may lead to complications such as heart attack, stroke, kidney failure, leg amputation, vision loss, and nerve damage [1]. Most diabetes patients are affected by type 2 diabetes mellitus (T2DM), a metabolic disorder that is often coupled with insulin resistance that affects the way the body metabolises its important source of fuel, glucose [2]. As reported by the International Diabetes Federation (IDF), T2DM comprises approximately 90% of all cases of diabetes, and to date, it is estimated that 15 million people are affected globally [3]. Previously, T2DM had only been diagnosed in older adults, but surprisingly, the current statistics show that T2DM is becoming more prevalent among children and adolescents due to escalating obesity and overweight incidences among the youth [1]. While current T2DM therapies involving the increase of insulin secretion have shown therapeutically beneficial effects, these are often accompanied by undesirable side effects such as hypoglycaemia and weight gain. Due to the reported adverse side effects, most of these treatments are unsatisfactory with regards to the prevention of complications and preservation of quality of life [4]. Thus, there is a significant medical need for the discovery of new and effective anti-diabetic agents for the treatment of T2DM.

α-Glucosidase is an enzyme that catalyses the final steps in the digestion of carbohydrate; hence, α-glucosidase inhibitors could retard the catabolism of dietary carbohydrates to suppress postprandial hyperglycaemia. There are arguments that α-glucosidase inhibitors such as acarbose (Glucobay) and miglitol (Glyset), although effective in decreasing the absorption of glucose by interfering with the action of α-glucosidases in the small intestinal mucosa, are often associated with abdominal bloating, diarrhoea, and flatulence [5]. α-Glucosidase inhibitors also raise post-meal levels of glucagon-like peptide-1 (GLP-1), an incretin hormone secreted by the intestine following the ingestion of various nutrients to stimulate insulin secretion and inhibit glucagon release, which slows the gastric emptying process and suppresses appetite [6]. This means that they do not increase the likelihood of weight gain, unlike sulfonylureas and thiazolidinediones [7].

Since 2006, dipeptidyl peptidase-4 (DPP-4) inhibitors have become a new class of agents that are proven to be an effective treatment of diabetes by improving glycaemic control [8]. DPP-4 inhibitors target DPP-4, a serine protease enzyme which deactivates two potent stimulators of insulin secretion, GLP-1, and glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide or GIP) [9]. Like GLP-1, GIP also helps to delay digestion and decrease appetite. However, both hormones are rapidly cleaved to their inactive forms by the enzyme DPP-4, thus, reducing their potency in preventing diabetes-related complications. Therefore, it is important to note that inhibition of DPP-4 is compulsory to increase levels of endogenous incretin hormones GLP-1 and GIP for the treatment of diabetes [10].

Chalcone is a small bioactive molecule composing of 1,3-diarylprop-2-en-1-one framework and is one of the abundant secondary metabolites of terrestrial plants and precursors of flavonoid biosynthesis [11], [12], [13], [33]. These molecules have been receiving great attention by the scientific community due to its simple chemistry, ease of synthesis, diversity of substituents, safety, and a vast number of recognized biological activities, including anti-obesity, anti-hypertensive and antidiabetic activities [13], [14], [15]. Several reports even indicate that chalcones may inhibit the enzymes α-amylase [16], [17], [18], [19] and α-glucosidase [16], [20], [21], [22], [23], [24]. Seo et al. (2005) reported aminated series of chalcone exhibited greater inhibition of three glycosidase enzymes (α-glucosidase from baker’s yeast, α-amylase from Bacillus licheniformis and β-amylase from barley) over other chalcone derivatives. The α-glucosidase inhibitory was then improved progressively when the aminated series were chemically modified into sulfonamide chalcones, which shown 150-fold stronger suppression than acarbose [25].

Sulfonamide, too, has received a lot of attention and is used as an intermediate functional group in many therapeutic drugs [26]. Several synthetic pharmacological agents that consist of a sulfonamide group possess anti-bacterial [27], antimalarial [28], diuretic [29], anti-rheumatic [30], and anti-retroviral properties [31]. Previous studies also reported that sulfonamide-containing compounds are essential for DPP-4 inhibitory activity [32].

Moreover, Rocha et al. (2019) investigated the effect of an extra double bond on the enone linker chain of the synthesized chalcone derivative, the diarylpentadienone against α-glucosidase [33]. Results revealed a slight improvement in the inhibitory activity of diarylpentadienones when compared to its chalcone derivative and the standard α-glucosidase inhibitor (AGI), acarbose. Recently, researchers have discovered diarylpentadienone analogues along with their various pharmacological activities, including promising anti-inflammatory property, significant anti-cancer effect towards leukaemia and breast cancer, excellent anti-microbial, anti-fungal, and anti-rhinovirus properties, and as an effective antioxidant [34], [35], [36], [37], [38], [39]. Despite the numerous bioactivities of diarylpentadienone derivatives, to the best of our knowledge, there is very little scientific information with regards to their potential as an anti-diabetic drug.

Thus, in continuation of our endeavors toward exploration of the therapeutic potential and clinical implication of diarylpentadienones particularly as α-glucosidase and DPP-4 inhibitors, we herein report the design, synthesis, in vitro biological evaluation, toxicity profiling using zebrafish in vivo animal model, and molecular docking of a new series of integrated sulfonamide-containing diarylpentadienones as potential anti-diabetic agents for the treatment of T2DM.