Pyrimidine as an Antidiabetic Derivative Targeting a-Amylase and a-Glucosidase Inhibitors: A Mini-Review

Birajdar Savita, Deepa Korawar, Dr Somashekhar M Metri*, Dr R B Kotnal, Santosh Metre, and Shilpa Muchandi - Department of Pharmaceutical Chemistry, BLDEA’s Shri Sanganabasava Mahaswamiji College of Pharmacy and Research Centre, Vijayapur-586101

Abstract

The rise of scourges, several infectious diseases, and a variety of diseases necessitate the development of new pharmacological innovations using activated nitrogen-based compounds. All living things have the pyrimidine component, which has several important biological characteristics. This work outlines a straightforward, synthesized approach for creating heterocyclic components with several nitrogen-rich atoms acting as crucial components for creating new diabetic medications. A key factor in reducing hyperglycaemia after meals in diabetes patients is the blocking of α-amylase (α-Amy) and α-glucosidase (α-Gls). In this scenario, the strongest anti-diabetic activity of α-glucosidase was shown by compounds 47-91, while α-amylase was shown by pyrimidine compounds 1-46. The results of this review demonstrate that this category of drugs has significant inhibitory efficacy towards this enzyme.

Keywords: Pyrimidine, α-amylase, α-glucosidase, Antidiabetic activity

Graphical Abstract

Introduction

The study of hetero cyclic chemical structure is the most complex and diverse area of organic science, and it is rapidly growing because of the wide range of applications these molecules have in industry, agriculture, and medicine.¹ In nature, N-heterocyclic compounds and their derivatives are extensively found. They serve as the skeletal pieces for many biological compounds, such as antibiotics as well as vitamins, hormones, enzymes, and alkaloids.² Nitrogen-based compounds are a special kind of heterocyclic scaffold because of both their biological and pharmacological characteristics.³ Pyrimidines are compounds that can be discovered in cells of every kind and the tissues of specimens, which explains their significance for medicinal chemical research. Pinner began his studies in 1884 by producing pyrimidine derivatives by condensing amidines and ethyl acetoacetate. Their chemical similarity to amidine is what gave rise to the term “pyrimidine.” ⁴ Pyrimidine, a nitrogen-containing compound that has a hydrogenated (pka value of 1.23, is less alkaline compared to pyridine and more difficult to N-alkylate and to N-oxidize.⁵

Recently discovered findings that specific pyrimidine-fused derivatives, which are vital for cell life, significantly inhibit mammalian gβ-glucosidaseenzyme have greatly increased our understanding of both DNA and RNA.^4,5 Similarly like the chemical compound pyrimidine is a heterocyclic hexagonal aromatic circle that contains two nitrogenous atoms at sites 1 and 3. The size of these categories varies according to the number of distinct organic and inorganic chemicals that include pyrimidines.⁶ The synthetic heterocycle, also known as the pyrimidine molecule, is composed of two nitrogen molecules and four carbon atoms. Numbers are allocated to atoms in clockwise order. Locations 1 and 3 contain the atoms of nitrogen. Carbamoyl phosphate is the source of carbon 2 and nitrogen 3.⁷

Uracil, cytosine, and thymine are the main pyrimidines that make up the uridine, cytidine, and thymidine ribonucleosides, as well as their corresponding deoxynucleotides, respectively. Cytosine and thymine are the fundamental components of the genetic material, while cytosine and uracil are found in strands of RNA.⁸

Pyrimidine derivatives are essential for several biological activities, such as anticancer,⁹ anti-HIV, antiviral,¹⁰ anti-histaminic,^11, and antibiotic.¹² The different modifications that must be introduced to a scaffolding continue to be a fascinating subject for medicinal chemistry researchers due to their diverse biological effects

A common metabolic illness that causes hyperglycemia and its aftereffects is type 2 diabetes mellitus. Globally, over 537 million individuals between the ages of twenty and seventy are impacted; by the years 2030 and 2045, that figure is anticipated to increase to 643 million and 783 million individuals, respectively.¹⁴ Some pyrimidines have anti-glucosidase and diabetes-related effects, and some are produced as α-glucosidase/α-amylase blockers. It has been shown that pyrimidines, particularly pyrimidine-fused heterocycles, are highly effective inhibitors of enzymes for diabetes.¹⁵

Alpha-amylases are calcium metabolic enzymes that are vital to human metabolism because they hydrolyze starch, amylopectin, amylose, glycogen, and maltodextrins. Studies are being conducted to lower the amylase protein’s function to control hyperglycemia.¹⁶ By inhibiting carbohydrase-related enzymes, among which are α-amylase and α-glucosidase, medicines like miglitol, acarbose, and voglibose decrease the taking in of glucose and reduce the risk of being diagnosed with type 2 diabetes ¹⁷

This work finds, creates, and assesses dihydropyrimidines through wet lab and computational approaches. The targets of proteins are identified and localized by in silico computational modeling.¹⁹

Pyrimidine as an Antidiabetic Agent

A. Alpha amylase inhibitor

Bharathi A et al. (2014) utilized synthetic compounds 1 and 2, and the inhibiting effect of α-amylase and α-glucosidase was assessed in vitro.²¹

Naveen K et al. (2016) produced components 3 and 4, which exhibit excellent α-amylase blocking inhibition properties.²²

Nabil S et al. (2018) reported that molecules 5 and 6 had strong blocking effects towards the amylase enzyme when the α-amylase blocking behavior of the curcumin pyrimidine derivatives at varying doses was investigated. 

Reddy BN et al (2019) described several pyrazolo[3,4-d] amide scaffolds that were created and tested for whether they could block α-amylase in vitro. Findings showed that analogs 7 and 8 were highly active and efficient ²⁴

Kalsoom S et al. (2021): created and evaluated fusing pyrimidine derivatives’ anti-diabetic properties; molecules 9 and 10 performed well since they had pyridine and a thino-pyrimidine scaffolds ²⁵

Hajlaoui A et al. (2021): was created by synthesis Triazole, pyranotriazolopyrimidines, and pyranotriazolopyrimidines, all have possible antidiabetic effects. A novel series of compound 11 was created using a simultaneous reactivation technique.²⁶

Arshad U et al. (2021): generated compounds 12 and 13 exhibited good to mild α-amylase inhibition activity, indicating promise for MTT cytotoxic and anti-diabetic tests.²⁷

Naik MD et al. (2021): The α-glucosidase protein can be inhibited more effectively by synthetic compounds than by the α-amylase enzyme.²⁸

Khasimbi S et al. (2021): was produced as Compounds 16 and 17 primarily stop the α-amylase enzyme from working.²⁹

Mehrabi M et al. (2021)reported α-that Glu and α-Amy enzyme functioning has been determined to be reduced by curcumin-based pyrano[2,3-d] pyrimidine substitutes, including compounds 18 and 19, showing the strongest inhibition of the α-Amy enzyme.³⁰

Ilyas U et al. (2022) introduced chemicals 20 and 21, which were found to have strong antidiabetic potential because of their α-amylase inhibition action.³¹

Pansuriya K et al. (2022): synthesised molecules 22 having urea-based pyrimidine groups and azepino and indole rings, shown effective α-amylase inhibition.³²

El-Khateeb AY et al. (2022): produced chemicals 23 and 2,4, which showed the strongest effects on the α-Amylase activity ³³

Gupta T et al. (2023) reported that Compounds 25 and 26 showed solid activity when examined in terms of their α-amylase inhibitory action (3,5-dinitro salicylic acid).³⁴

Zala AR et al. (2023): synthesized compounds 27 and 28, which showed good to excellent inhibitory effects when assessed using their in vitro α-amylase inhibitory activity at varying dosages.³⁵

Banupriya S et al. (2024): matched to the original reference, acarbose, the latest synthesized chemical 29 demonstrated antidiabetic efficacy. Improved - α-amylase inhibition was demonstrated by derivatives ³⁶

Almehizia AA et al. (2024): reported in comparison with conventional acarbose at an identical quantity, it was discovered that N-(4-chlorophenyl)-pyrazolo[1,5-a] pyrimidine derivatives 30 and 31 had the strongest blocking impact on α-amylase.³⁷

Zaman H et al. (2024): In compounds 32 and 33, it was discovered that substituents placed at the para-position of phenyl rings greatly increase the inhibitory effect of the α-amylase enzyme.³⁸

Khalid T et al (2024) showed great promise in this field after synthesizing pyrimidine derivatives 34 and 35 and assessing their in vitro anti-diabetic efficacy against the α-amylase enzyme.³⁹

Seboletswe P et al. (2025): created substances 36 and 37 that were scientifically assessed for their α-amylase in vitro would significantly impact their α-amylase.⁴⁰

Rashid M et al. (2025) reported component 38 to be more effective when evaluated for its capacity to avoid type II diabetes. The targeted chemical showed effective suppression in 38 anti-diabetic experiments ^1. 

Elsayed DA et al. (2025): described compounds 39 and 40 showed the strongest binding ability when the α-amylase inhibition rate was calculated using acarbose as the baseline value.⁴²

Sakarya MT et al. (2025) showed that synthesized compounds 41 and 42 were more potent inhibitors than reference acarbose towards αα-amylase^4.3

Yousefi A et al. (2025) reported that to reduce hyperglycaemia after a meal, the investigation sought to develop novel anti-diabetic curcumin derivatives 43 and 44 that have inhibitory activities towards α-amylase and α-glucosidase.⁴⁴

Fatima M et al. (2025): identified the diabetes prevention effects of novel synthesized pyrano[2,3-d] pyrimidines were assessed in vitro in this study, and the results demonstrated substantial inhibitory impact in combinations with α aα-amylasesuppression. ⁴⁵

B. Alpha-glucosidase inhibitor

Yousefi R et al. (2012) recently created substances 47 and 48 that were tested in their capacity to interfere with the α-glucosidase enzymes in mice and yeast.⁴⁶

Yar M et al. (2014): Innovative substances 49 and 50 were investigated regarding being ability to interfere with α-glucosidase activity, and the produced compounds demonstrated encouraging α-glucosidase action.⁴⁷

Suresh L et al. (2016) reported that, based on their respective Michaelis-Menten kinetics results, it was discovered that the compounds tested 51 and 52 preferentially inhibited α-glucosidase activity. 

Sahu M et al (2016) found that substances 53 and 54 exhibited strong α-glucosidase inhibiting properties and could be a useful anti-diabetic medication.⁴⁹

Beena KP et al. (2016):  produced several dihydropyrimidine derivatives and assessed their ability to block the α-glucosidase action ⁵⁰

Gong Z et al. (2017) recently produced 2-substituted-4,6 diarylpyrimidines that have been studied for their ability to inhibit α-glucosidase in vitro. The most efficient agents towards α-glucosidase were 56 and 57.⁵¹

Ur Rehman T et al. (2017) studied molecules 58 and 59 that were evaluated for the presence of α-glucosidase. These substances showed good mild to moderate inhibitory potential, according to the data.⁵²

Spasov AA et al. (2017): evaluated the analyzed chemicals’ anti-diabetic qualities by looking at how they inhibited diabetes towards α-glucosidase glycogen phosphorylase, and dipeptidyl peptidase 4 (DPP4). 60 and 61 are α-glucosidase inhibiting agents ⁵³

Adib M et al. (2018) studied the synthetic chemicals 62 and 63 and their in vitro α-glucosidase inhibitory activities, have were contrasted to acarbose as a standard, showing a  good reduction of ⁵⁴

Fandakli S et al. (2018): Compounds 64 and 65, which were not assessed for their α-glucosidase enzyme activity, showed a stronger inhibitory impact than acarbose, and both α-glucosidase inhibitors are employed as antidiabetic medications⁵⁵

Thakur RK et al. (2018) were assessed for their ability to block the α-glucosidase molecule, and metabolites 66 and 67 showed ⁵⁶

Mehraban MH et al. (2019) reported that our PFH ligands were the subject of a computer simulation to investigate their attachment locations on hMGAM, an enzyme that breaks down carbohydrates in the human lumen. ⁵⁷

Bule MH et al. (2019): evaluated the inhibiting effect of produced compounds in vitro via contrasting between the studied pyrimidine analogs and the conventional medication acarbose 70 and 71.⁵⁸

Badria FA et al. (2019) determined that the component with the highest α-glucosidase efficiency is 72.⁵⁹

Abuelizz HA et al. (2019): produced, identified, and put through an α-glycosidase inhibiting test 73 and 74 substances that exhibited over 50% of the typical level reduction.⁶⁰

Naik MD et al. (2020) reported that the manufactured substrates are much better compared to αthe -mα-amylasenhibitor at suppressing the production of α-glucosidase.⁶¹

Peytam F et al. (2021) determined substance 77 and 78 to be the strongest α-glucosidase inhibitors among the substances that could be made from the following compounds: [4,5] imidazo[1,2-a] pyrimidines.⁶²

Ilyas U et al. (2022) examined selected substances 79 to identify their antidiabetic properties using the α-glucosidase inhibitory tests, which produced findings.⁶³

Trifonov RE et al. (2023) created alpha glucosidase blockers that have similarities to dihydrotetrazolopyrimidines 80 and 81. These substances demonstrated superior α-glucosidase inhibit action.⁶⁴

Kamat V et al. (2023) reported a simple and efficient method for synthesizing functionally varied 1,2,3,4-tetrahydropyrimidine5-carboxamide compounds was developed. Compound 82 demonstrated good blocking compared to its derivatives.⁶⁵

Ali SP et al. (2024) identified dihydropyrimidone variants that showed encouraging α-glucosidase inhibitory action, with components 83 and 84 recognized as strong competitively inhibition.⁶⁶

Almehizia AA et al. (2024) evaluated the two pyrazolo[1,5-a] pyrimidine derivatives 85 and 86 with the greatest inhibition α-glucosidase activity were tested for their anti-diabetic properties.⁶⁷

Cele N et al. (2024) reported the OCF3-substituted molecule was the most powerful α-glucosidase antagonist in general, and compounds 87 and 88 were also more effective than acarbos.⁶⁸

Herfindo N et al. (2025) identified the α-glucosidase inhibition action of a variety of pyrimidinyl-piperazine carboxamide derivatives which were produced was examined. In entirety, the produced compounds 89 and 90 demonstrated good inhibition of α-glucosidase.⁶⁹

Kobesy MR et al. (2025) compound 91 showed higher α-glucosidase inhibitory activity.⁷⁰

Conclusion

We have investigated the pyrimidine molecule and its several synthetic alternatives in this extensive systematic study, exploring their possible medical uses. With values ranging from 1 to 46 for α-amylase inhibition and from 47 to 91 for α-glucosidase inhibition, our results showed a notable variation in the percentages linked to the availability of anti diabetic drugs. Finally, it was determined that pyrimidine and its analogs, which specifically inhibit the metabolic enzymes α-amylase (α-Amy) and α-glucosidase, are essential for the management and treatment of diabetes following a thorough review of the scientific literature. Incredibly beneficial possibilities for further research and implementation of this chemical in future treatment techniques targeted at fighting diabetes are suggested by this persuasive data.

Acknowledgement

We express our gratitude to the administration, principal, and head of the SSM College of Pharmacy and Research Center at BLDEA in Vijayapur, Karnataka, 586103. Additionally, we are grateful to Dr. R. R.B.B.Kotnal and Dr. Somashekhar Metri of the Pharmaceutical Chemistry Department.

Conflict Of Interest

All the authors have no conflicts of interest.

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Author Biographies

Ms. Birajdar Savita, PG scholar in the Department of Pharmaceutical Chemistry at BLDEA’s Shree Sanganabasava Mahaswamiji College of Pharmacy and Research Centre, Vijayapura, Karnataka. I have received my B-Pharmacy degree from Dr. Babasaheb Ambedkar Technological University, Lonere, Maharashtra. My research interest primarily focuses on drug design, discovery, metabolite characterization, and QSAR. My current review focuses on the design of numerous derivatives of Pyrimidine as an antidiabetic agent. I am publishing a few review papers in reputed journals and participating in postgraduate research work and national and international conferences, and webinars.

Ms. Deepa Korawar, PG scholar in the Department of Pharmaceutical Chemistry at BLDEA’s Shree Sanganabasava Mahaswamiji College of Pharmacy and Research Centre, Vijayapura, Karnataka. She received her B-Pharmacy degree from Rajiv Gandhi University of Health Sciences, Bengaluru, Karnataka. Her primary research interests include the design and synthesis of novel bioactive compounds, drug metabolism, and in vitro evaluation of therapeutic agents. She is publishing a few review papers in reputed journals and actively participating in postgraduate research work and national and international conferences.

Dr. Somashekhar M Metri (M.Pharm Ph.D.) is currently serving as an Associate Professor and HoD in the Department of Pharmaceutical Chemistry at BLDEA’s Shree Sanganabasava Mahaswamiji College of Pharmacy and Research Centre, Vijayapura, Karnataka. With over 13 years of teaching and research experience. He has specialized in the area of Drug design and docking studies, synthetic chemistry,2D-QSAR study st udy of, SAR studies of synthesized compounds, Handling of analytical instruments, computer-aided drug design studies, and analysis of pharmacological activities of newly synthesized compounds. He works as a reviewer for more than 20 various peer-reviewed national and international journals, like WoS, Scopus, and Elsevier journals. Organized more than 12 conferences, seminars as a secretary, participated in more than 55 various national and international seminars, conferences, and faculty development programs. Appointed as Bentham Science Journal Ambassadors year 2019-20.

Dr. R.B.Kotnal M.Pham, Ph.D., is currently serving as a Professor and Director of BLDEA’s Shree Sanganabasava Mahaswamiji College and Research Centre, Vijayapura, Karnataka. With over 27 years of teaching and research experience. He specialized in the synthesis of heterocyclic compounds and, development of novel drug delivery systems. Dr. R.B.Kotnal published more than 24 research papers in reputed journals like The Eastern Pharmacist, Indian Pharmacist. Education, Indian drugs, E J Chem, International Journal of Research in Pharmacy and Life Sciences, etc..Participated in workshops, Qu Quality Improvement Program, the  Faculty Development Program sponsored by the All India Council for Technical Education (AICTE), and the Indian Society for Technical Education( ISTE).

Mr. Santosh Metre,  student of M Pharm, Department of Pharmaceutical Chemistry at BLDEA’s Shree Sanganabasava Mahaswamiji College of Pharmacy and Research Centre, Vijayapura, Karnataka. He pursued his B-Pharmacy degree from Rajiv Gandhi University of Health Science,se Bengaluru, Karnataka. His research interest focuses on medicinal chemistry, analytical chemistry, biopharmaceutics, and pharmacokinetics. He is actively involved in postgraduate research work.

Ms. Shilpa Muccha ndi,  student of M Pharm, Department of Pharmaceutical Chemistry at BLDEA’s Shree Sanganabasava Mahaswamiji College of Pharmacy and Research Centre, Vijayapura, Karnataka. She pursued her B-Pharmacy degree from Rajiv Gandhi University of Health SSciencesBengaluru, Karnataka. She has major areas of interest in arch, including medicinal chemistry, molecular mechanisms in drug design, and drug design and discovery.

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