Introduction As per WHO report
As per WHO report, in 2014 more than 422 million peoples were living with diabetes and according to International Diabetes Federation, by 2045 this figure would reach 693 million [1,2]. Diabetes, a fast growing major health problem, is common chronic, metabolic disease characterized by increased level of plasma sugar by lack or ineffective use of insulin in body . Diabetes has grouped into three categories, Type I Diabetes mellitus (T1DM), Type II Diabetes mellitus (T2DM) and Gestational Diabetes Mellitus (GDM). About 80%–90% of all diabetic cases have attributed by T2DM and remaining by T1DM and GDM. Medication in T2DM needs reduction of hepatic glucose production, enhancement of insulin action, intensification of insulin secretion from β-pancreatic LY3039478 sale or inhibition of carbohydrate digestive enzymes (Glycosidase inhibitors) [, , , , ]. Non-management in diabetic conditions may lead to complications such as kidney diseases, nervous system diseases, leg amputation, heart diseases and blindness .
The prime action of α-glucosidase inhibitors occurs on hyperglycemia without direct effects on secretion of insulin. These are first line oral sugar lowering agents. In mild diabetic conditions, α-glucosidase inhibitors are used as monotherapy, while in severe diabetes, it is used as combination therapy with insulin or other drugs. Currently, carbohydrate mimics acarbose, voglibose and miglitol are in clinical use that bind reversibly itself to α-glucosidase and discontinue the saccharide hydrolysis. Side effects of using these drugs are mainly gastrointestinal which include nausea, bloating, diarrhea, abdominal pain and flatulence [, , , ]. To overcome these side effects, researches are now focused towards exploring new heterocyclic entities which if studied systematically may emerge as suitable candidates for glycosidase inhibitors. Due to wide-ranging and versatile biological properties, heterocyclic systems are visualized as an appealing area of interest for most medicinal chemists, and thus heterocyclic scaffolds have been privileged core part of majority of medicinal compounds. Heterocyclic derived compounds can be budding anti-diabetic agents.
Previously, sugar based compounds have been studied predominantly as potential α-glucosidase inhibitors. In 2006, Carvalho and coworkers published a review regarding α- and β-glucosidase inhibitors . In 2015, Ghani presented a detailed review on α-glucosidase inhibitors stressing the need for further research developments in this area . A review on heterocyclic α-amylase and α-glucosidase inhibitors (natural and synthetic) was also covered by Manayi and coworkers which also included literature till 2015 . Recently, Ma and coworkers gave a review on α-glucosidase inhibitors covering majorly sugar-mimics compounds . Singh and coworkers review deals with various aspects of anti-diabetic agents, i.e., enzyme targets such as Aldose reductase, DPP4, GPCR, PPARγ, GP, PEPCK, PTP1B, SGLT etc. . Heterocycle based α-glucosidase inhibitors have gained momentum and various heterocyclic substrates have been employed for exploring new entities. Thus, this review highlights the recent progress from 2015 onwards which are not covered elsewhere and may contribute in search for promising heterocyclic based new clinical candidates as α-glucosidase inhibitors. The review is focused on synthetic heterocyclic derivatives and hybrids for α-glucosidase inhibition with Structure Activity Relationship (SAR) studies along with interactions displayed from docking results; wherever available from literature.
Synthetic heterocyclic α-glucosidase inhibitors
Acknowledgments M.D. is grateful to the Babasaheb Bhimrao Ambedkar University, Lucknow and University Grants Commission for the fellowship. P.G. thanks Department of Science and Technology (DST), New Delhi, for financial support (DST-Inspire Faculty Project, IFA-13, CH-110) and the Babasaheb Bhimrao Ambedkar University, Lucknow, for infrastructure and facilities. Authors are thankful to reviews for valuable comments which have helped to improve presentation of the manuscript.