Diabetes mellitus (DM), a chronic metabolic disease of carbohydrate metabolism, certainly remains one of the most debilitating non-communicable health challenges around the globe. The metabolic disorder is generally characterized by elevated blood glucose levels [[1], [2], [3], [4]]. Type 1 diabetes patients fail to secrete insulin, whereas, insulin resistance and an impaired insulin secretory system can cause type 2 diabetes [5,6]. According to the International Diabetes Federation, 536.6 million individuals worldwide had type 2 diabetes in 2021, making up around 90 % of all occurrences of the disease and is predicted to go up to 783.2 million by 2045 [7,8]. DM severely impacts millions of people worldwide and leads to numerous other serious health problems such as kidney diseases, cardiovascular diseases, obesity, blindness and hypertension adding significant cost to the healthcare system. One of the strategies to manage the hyperglycaemic condition in type 2 patients includes the inhibition of digestion and absorption of dietary carbohydrates [9].

In this perspective, α-glucosidase and α-amylase are the two crucial saccharides hydrolyzing enzymes having an impact on the digestion and breakdown of the carbohydrates [10,11]. The α-glucosidase enzyme is responsible for the hydrolysis of α-(1,4) linkages between the monosaccharide units and is located on the small intestinal brush border [[12], [13], [14]]. The α-amylase catalyzes the metabolic route of breakdown of starch into simple sugar units and is found in the saliva of some mammals, including humans [15,16]. The human α-amylase contains Ca2+ ions in the active binding site. The pancreas and salivary glands secrete this enzyme in addition to its occurrence in bacteria, plants, and the human body [17,18]. The enzyme facilitates the conversion of starch to glucose and maltose [19]. Due to its effectiveness in cleaving the α-(1,4) linkages of starch carried out by hydrolysis, this enzyme plays a significant role in carbohydrate metabolism. Diabetes, obesity, neuropathy, nephropathy, retinopathy and dental diseases are just a few of the major health issues that are the common causes of elevated blood glucose levels [[20], [21], [22]]. Type 2 diabetes is effectively treated by inhibiting these two enzymes so to prevent or delay the breakdown of carbohydrates as well as the subsequent production and uptake of glucose after meals [23]. The current anti-hyperglycaemic drugs for type 2 diabetes include acarbose, miglitol, and voglibose [24,25]. Acarbose has ability to inhibit both α-glucosidase and α-amylase enzymes while, miglitol and voglibose solely inhibit α-glucosidase enzyme [26]. These drugs work well to manage postprandial hyperglycemia, but their gastrointestinal side effects make them unsuitable for long-term use [27]. Various heterocyclic compounds including coumarins, triazines, quinazolines, pyrimidines, thiazoles, isatins, indoles, imidazoles, carbazoles, xanthones, quinolines, acridines, oxadiazoles, triazolothiadiazoles and triazolothiadiazines etc. [[28], [29], [30], [31], [32]] have been successfully identified as promising α-glucosidase inhibitors, however, the undesirable side effects associated with the marketed drugs/inhibitors provide a continuous impetus to explore the wider chemical space in the pursuit of new drug candidates.

Isobenzofuranones, also known as phthalides, are important heterocyclic organic compounds with diverse medicinal applications [33]. They occur in numerous natural products and display a wide spectrum of biological activities. Isobenzofuranone derivatives have been investigated for their novel therapeutic uses and exploited to deliver potent antileishmanial, antioxidant, antidiabetic, antimicrobial, anticoagulation, and antiplatelet activities [[34], [35], [36], [37], [38], [39]]. They are proved effective antifungal agent and inhibit biofilm formation [40]. Isobenzofuranones have also displayed potential in the management of circulatory and heart diseases [41]. Fig. 1 illustrates selected examples of bioactive natural isobenzofuranones.

In view of the aforementioned literature data and our continuous efforts in this research area [32,[42], [43], [44]], the present work focuses on the identification and development of new anti-diabetic drug candidates based on isobenzofuranone core. A robust, reliable and powerful Suzuki-Miyaura cross-coupling reaction [45,46] was used to construct new carbon‑carbon bonds producing a concise library of isobenzofuranone products from 5-bromoisobenzofuran-1(3H)-one and boronic acids. In vitro inhibitory assays against α-glucosidase and α-amylase were performed in order to identify the lead molecules which were examined for their anti-diabetic potential in vivo. The mode of inhibition for potent compounds was also revealed whereas in silico molecular docking and dynamics simulations supplemented the in vitro/in vivo results. Finally, ADME properties were calculated for the lead inhibitors and results demonstrate that the identified compounds meet the most suitable druggable criteria.