Received date: June 01, 2015; Accepted date: July 17, 2015; Published date: July 25, 2015
Citation: Aboul-Enein HY, El Rashedy AA (2015) Benzimidazole Derivatives as Antidiabetic Agents. Med chem 5:318-325. doi: 10.4172/2161-0444.1000280
Copyright: © 2015 Aboul-Enein HY, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Benzimidazoleis an important pharmacophore which was included in several biologically active compounds resulted in the development of several classes of drugs. This review discusses the synthesis of benzimidazole derivatives as a target agents for antidiabeticby different mechanism such as peroxisome proliferator – activated receptor α transcriptional activity, glycosidases receptor, dipeptidyl peptidase IV, glucokinase, human glucagon receptor (hGCGR) antagonist , aldose reductase enzyme and stearoyl- CoA desaturase.
Diabetes mellitus (DM) is a chronic metabolic disease which result due to no production of insulin causing type 1 DM or due to partial and/or insufficient production of insulin causing type 2 DM. Furthermore , insulin resistance cause hyperglycemia and diabetes due to the inability of the cells to use insulin properly and efficiently. Some to the serious complication of diabetes include nephropathy, retinopathy, neuropathy, foot ulcers among other symptoms . One of the most widely used antidiabetic agents are the sulfonylureas which act through the stimulation of the pancreatic β-cells for the secretion of insulin. Another class of antidiabetic agents are thiazolidinediones e.g. glibenclamide, ciglitazone and troglitazone. These drugs stimulate insulin secretion and therefore are effective in treatment of in a type-2 diabetic patients. Metformin which belongs to the biguanides group which enhance insulin action at the post receptor level in peripheral tissues such as muscle .
“Shingalapur et al.  synthesized a series of 1,3,4-oxadiazoles derivatives containing 2-mercapto benzimidazole moiety and screened for in vivo antidiabetic activity using oral glucose tolerance test (OGTT)”. Some of these derivatives showed improved reduction in blood–glucose levels compared with glibenclamide (Scheme 1).
R= 4-OH,2-OH,Fufurayl, naphthalen-2-ol
Some new benzimidazole containing thiazolidinone 2, 3 were also reported for anti-diabetic activity. Both compounds were found to be more potent in hyperglycemic and normoglycemic models at a dose of 50 mg/kg .
A series of bis-benzimidazole derivatives were synthesized and found that compound 4 has showed significant antidiabetic activity when compared to glibenclamide as standard drug  (Scheme 2).
Type 2 diabetes mellitus (T2DM) is characterized by defects in insulin secretion and insulin sensitivity [6,7]. Insulin resistance by itself will not result in T2DM unless β-cell secretion of insulin is decreased. Based on the Centers for Disease Control and Prevention National Diabetes Fact Sheet in 2007 , there were 23.6 million Americans with diabetes, of whom 90% to 95% have T2DM.
Peroxisome Proliferator Activated Receptors (PPARs) act as regulators of lipid and glucose metabolism. This resulted in the development of synthetic drugs which represent a potential tool for therapeutic intervention in type 2 diabetes mellitus (T2DM). PPARα 5 is ligand belonging to the nuclear receptor superfamily. The target genes of PPARα are group of genes that participate in various aspects of lipid catabolism such as (a) fatty acid uptake through membranes, (b) fatty acid binding in cells, (c) fatty acid oxidation in microsomes, peroxisomesand mitochondria, and (d) lipoprotein assembly and transportation . The significance of PPARα in physiological and pathophysiological states is the fact that they are considered as a molecular targets for the lipid-lowering fibrate drugs and insulinsensitizing thiazolidinedione (TZD), respectively  .
“Minoura et al found that 3-(2,4-dichlorobenzyl)-2methyl-N- (pentylsulphonyl)-3H-benzimidazole-5-carboxamide,6, improve insulin resistance in mammalian animal model through activation of PPAR-GAMA (Peroxisome proliferator-activated receptor)-mediated transcripational activity thus compound 6 is considered as a novel therapeutic candidate for treatment of type 2 diabetic patients” 
Sime et al.  carried out an optimization study of PPAR gamma activity which lead to the identification of GSK1997132B , 7 as shown in scheme 3, which it is a potent, metabolically stable and centrally penetrate PPAR γ - partial agonist .
Scheme 3: Reagents and conditions: (a) SOCl2, MeOH, 24 h, reflux; (b) (3,5-difluoropyridin-2-yl)methanamine , DIPEA, THF, 17 h, reflux; (c) SnCl2.2H2O, EtOAc, 2 h, reflux; (d) CH3COCl, DIPEA, 30 min, 0°C to rt; (e) AcOH, 18 h, reflux; (f) (i) LiOH, THF/water, 18 h, reflux; (ii) HCl; (g) (R)-1- phenylpropan-1-amine, HATU, DIPEA, DMF, 18 h, rt.
Goebel et al.  introduced different substitution on C-2 of the central benzimidazole ring of telmisartan for PPARγ activation. Compounds 8 a-i were evaluated in a differentiation assay using 3T3- L1 preadipocytes and a luciferase assay with COS-7 cells, transiently transfected with pGal4-hPPARγDEF, pGal5-TK-pGL3 and pRLCMV, as established models for the assessment of cellular PPARγ activation.” The alkyl series: iso-butyl (8b) ≤ tert-butyl (8c) <butyl (8a) demonstrated an increase in activity of the luciferase assay. Compound 8d with a phenyl group at C-2 was the most active compound with an EC50 value of 0.27 μM. 4-Hydroxylphenyl analog (8i) caused a drastic decrease in the activity. (EC50=5.8 μM) presumably due to hydrophilic repulsion. This assumption was verified by O-methylation as shown in compound 8h , which retained the activity (EC50=0.29 μM). The weak activity of the benzyl derivative 8e (EC50=1.4 μM) was abolished by an additional hydrophobic 4-chloro substituent (8g; EC50=0.55 μM) or an increase of the alkyl chain between the phenyl and the benzimidazole rings (8f; EC50=0.31 μM) .
R = (a) butyl ,(b) iso-butyl , (c) tert-butyl , (d) phenyl , (e) benzyl , (f) phenethyl ,(g) 4-chlorobenzyl , (h) 4-methoxyphenyl , (i) 4-hydroxyphenyl .
Insulin resistance in C57BL/KSJ-db/db mice (db/db mice) animal models was improved by 3-(2,4-dichlorobenzyl)-2-methyl- N-(pentylsulphonyl)-3Hbenzimidazole- 5-carboxamide (FK614), 9, through activation of PPARc-mediated transcriptional activity. Accordingly compound 9 is considered a lead and a novel therapeutic agent for treatment of type 2 diabetic patients .
Benzimidazole as Glycogen Activator
The regulation of hepatic glucose production is controlled mainly by glucagon and insulin , thus a fall in the plasma glucose levels cause the secretion of glucagon by the pancreatic alpha-cells. Glucagon activates its receptor which is a G-protein coupled receptor located in the liver, causing an increase of the hepatic glucose production through glycogenolysis and gluconeogenesis. In db/db  and ob/ob  diabetic mouse models, reduction of glucagon receptor expression with antisense oligonucleotides result in the antidiabetic effect. In type 2 diabetic patients, elevated glucagon levels lead to an increae of the hepatic glucose output causing hyperglycemia. Accordingly, both macromolecules and small molecules glucagon receptor antagonists have been investigated as potential treatments for type 2 diabetes . As a result Bayer developed the small molecule BAY-27-9955 which blocked glucagon-induced glucose production in healthy human volunteers .
Glucokinase (GK) is an enzyme which facilitate the phosphorylation of glucose to glucose-6-phosphateand occurs predominantely in the liver and pancreatic beta-cells . Glucokinase plays an important role in carbohydrate metabolism.Thus GK activation causes an increase in hepatic glucose uptake and utilization. It is of interest to mention that GK activity is related to increase insulin secretion in beta cells [21,22]. Accordingly, GK activators (GKAs) can act as hypoglycemic agents through the following mechanisms: i) an increase in the glucose uptake by the liver and ii) stimulating insulin secretion from pancreatic betacells. Based on this rationale, various small molecules were synthesized as GKAs [23–29].
New 2-(pyridine-2-yl)-1H-benzimidazole glucokinase activators were investigated. Through structural modification of benzimidazole lead to compound 11p(R) 10 which as identified from a highthroughput screening. Compound 11-p(R) 10 found to be a potent glucokinase activator 11p(R) (scheme 4). The compound also possesses an acute oral glucose lowering efficacy in rat OGTT model .
Scheme 4: Reagents and conditions: (a) Pd(PPh)2Cl2, Na2CO3, 80 °C, DME, H2O, 63%; (b) Pt/C, H2, MeOH, 85%; (c) TFA; (d) (CF3CO)2O, pyridine; (e) HNO3, 87% for three steps; (f) K2CO3, MeOH-H2O; (g) Boc2O, Et3N, CHCl3, 67% for two steps; (h) Cs2CO3, 4-fluorophenol, NMP, 80 °C, 85%; (i) Raney- Ni, NH2NH2, MeOH, 90%; (j) 2-pyridinecarboxaldehyde, EtOH, AcOH, 80 °C, 65%;(k) chiral separation by HPLC eluted with n-hexane/iPrOH (9/1v/v)/0.1% Et2NH; (b) Ac2O, pyridine
Several compounds with a cyclic amide or imide moiety on the benzimidazole ring were synthesized as potent GK activators . These compounds, exemplified by 13 were designed by removing the chiral center of (N-acetylpyrrolidin-2-yl)benzimidazole and lead to compound 12. Succinimide derivative 13 caused a significant decrease of the plasma glucosewhen administered at 1mg/kg po in rat OGTT, and demonstrated acceptable pharmacokinetic profiles in beagle dogs. Furthermore, X-ray crystallographic analysis of the GKA 3g/ GK protein complex revealed that compound 12 binds to the allosteric binding site of GK (Scheme 5).
Scheme 5: Reagents and conditions: (a) cat H2SO4, MeOH, reflux, 94%; (b) H2 (balloon), Raney Ni (cat), MeOH, THF, rt, 99%; (c) 2-picolinic acid, WSCI, pyridine, rt, 92%; (d) fuming HNO3, 0°C to rt, 85%; (e) phenol , K2CO3, DMF, 80 °C, 82%; (f) SnCl2-2H2O, HCl, MeOH, DMF, 80 °C; (g) SEMCl, NaH, DMF, rt, 73% in two steps; (h) LiAlH4, THF, 0°C, 80%;(i) imides, 40 wt % DEAD in toluene, PPh3, THF, rt. (J) TFA, H2O, rt.
Glycosidasesare group of enzymes responsible for the hydrolysis of gylcosidic bonds in complex carbohydrates. They recently became potential targets for the development of antidiabetic drugs.
2-Substituited benzimidazole derivatives were prepared by Jaladi et al.  and evaluated for their activity on yeast and rat intestinal α-glucosidase inhibition. Compound 14 exhibited 95.6% inhibition of yeast and rat intestinal α-glucosidase enzyme while compound 15 displayed 76% inhibition. Compound 14 was found to be the most potent inhibitor for intestinal α-glucosidase with IC50 value of be 99.4 μM. Compounds 14, 15 displayed significant antihyperglycemic activity in starch-induced postprandial hyperglycemia in rats .
Dipeptidyl peptidase IV (DPP-4) is a serine protease which has an intrinsic membrane glycoprotein and a serine exopeptidase that X-proline dipeptides from the N-terminus of polypeptides . DPP-4 rapidly cleaves and inactivates the incretin glucagon-like peptide 1 (GLP-1) in the blood. Drucker et al.  and Herman et al.  published reports indicating that the active form of GLP- 1 stimulates insulin release from beta cells in the pancreas , accordingly inhibition of DPP-4 can increase the levels of circulating GLP- 1 thus causing an increase insulin secretion and therefore can regulate blood glucose levels effectively.
Since the active form of GLP-1 stimulates insulin release from beta cells in the pancreas, inhibition of DPP-4 can increase the levels of circulating GLP- 1 thus causing an increase insulin secretion and effectively regulate blood glucose levels [34-36].
Structure-activity relationships (SAR) development led to the discovery of multiple compounds which are potent and selective for example 16, 17  (Scheme 6).
A series of substituted benzimidazole derivatives were synthesized and evaluated for their potential anti-diabetic properties . All the tested compounds showed anti-diabetic activity against DPP-IV and PTP-IB. Compound 17 showed inhibitory activity against PTPIB (1.64 %, 2.42 %) at 30 Μm doses and exhibited inhibitory activity against DPP-IV (3%) at 0.3 Μm doses.
Currently, research is focused on the development of non-peptide glucagon receptor antagonists. 2-(Benzimidazol-2-ylthio)-1-(3, 4- dihydroxyphenyl)-1-ethan one, NNC 92-1687 , 18 is the first nonpeptide competitive antagonist to human glucagon receptor which specifically bind to theglucagon receptor, and thus causing inhibition of glucagon-stimulated cAMP accumulation in cells expressing the glucagon receptor .
Compound 19 was the lead compound for this series which displayed promising in vitro potency and efficacy in vivo however it suffered from unacceptable pharamcokinetic profiles in preclinical animal studies and also poor human liver microsome stability, largely due to metabolic N-demethylation. Therefore, research was aimed at improving metabolic stability by introducing steric bulk near the site of metabolism resulted in a series of 4,6- disubstituted cyclic guanidine analogs which demonstrate improved metabolic stability, good rodent pharmacokinetic profiles, and excellent pharmacodynamic activity. Cyclic guanidine human glucagon receptor antagonists represented by the discovery of compound 20 which effectively caused blockade of glucagon induced glucose excursion in murine model, and also caused significant reduction in glucose levels in ob/ob/hGCGR efficacy model  (Scheme 7).
Scheme 7: Reagents and conditions: (a) NaH, MeI, DMF, rt; (b) SnCl2, 2H2O, DMF/water, 40 ° C (c) 4-trifluoromethylphenyl isothiocyanate, CH2Cl2, 40 °C, then Hg(OTFA)2, DMF, rt; d. methyl 4-bromomethylbenzoate, CH3CN, 110 ° C (e) n-propanol, Cs2CO3, Pd(OAc)2, 2-(di-tert-butylphosphino-1,1, -binaphthyl, toluene, 70 ° C; (f) (i) LiOH, dioxane/ water, 40 °C; (ii). 5-aminotetrazole, EDC, HOBt, DIEA, DMF.
Several acetic acid derivatives of [1,2,4]triazino[4,3-a] benzimidazole (TBI) were prepared and evaluated both in vitro and in vivo as selective aldose reductase (ALR2) inhibitors . Compound PS11, 21, possessed the highest inhibitory activity (IC50) 0.32 mM and was found to be effective in preventing cataract development in severely galactosemic rats when administered as an eye drop solution. Although all the compounds investigated were selective for ALR2, yet none of them inhibited appreciably aldehyde reductase, sorbitol dehydrogenase, or glutathione reductase  (Scheme 8).
Increasing obesity and other metabolic disorders such as type 2 diabetes in Western societies focused on the necessity to discover new pharmaceuticals for the treatment of these conditions [41,42]. An increase of the activity of stearoyl- CoA desaturase (SCD1), one of the essential enzymes in lipogenesis, which has been linked to the pathogenesis of obesity, metabolic disorders, dyslipidemia and type 2 diabetes [43,44]. SCD1 catalyzes the formation of a cis-double bond at the carbon-9 position of saturated fatty acyl-Coenzyme-A esters which is the rate-limiting step in the synthesis of mono-unsaturated 16:1 n-7 and 18:1 n-9 fatty acyl-CoAs . Different nutritional and pharmacological stimuli regulate the SCD1 expression [45,46]. SCD1- deficient mice were reported to exhibit reduced body weight, body fat mass, increased oxygen consumption and improved insulin sensitivity in a glucose tolerance test . Substantial research have been directed to develop small-molecule SCD1 inhibitors for the treatment of metabolic disorders.
Through computational drug design search a series of potent SCD1 inhibitors were developed which resulted in the discovery of SAR224 which possessed favorable vivo pharmacokinetics andpharmacology studies after oral administration to male Zucker diabetic fatty (ZDF) rats. Hence SAR224, represents a promising lead compound for further investigation of SCD1 inhibitors as potential treatments of diabetes and related diseases  (Scheme 9).
Reagents and conditions: (a) AcOH/H2O 80/20, 65°C, 90 min, 73%; (b) Na2S2O5 (1.3 equiv), DMF, 100°C, 1 h, 79%; (c) tert-Bt OH, EDC·HCl, DIEA, DMF, rt, 18 h, 95% (d) 2-aminomethyl-5- chlorothiophene.
Triglyceride (TG) synthesis is involved in several biochemical processes, such as energy storage in adipose tissue, muscle, and assembly of lipoprotein particles in the liver and small intestine. However, excess accumulation of TG can cause several disorders, such as dyslipidemia, obesity, insulin resistance, and hepatic steatosis. Therefore, inhibition of the synthesis of TG is considered as an efficient rationale for treatment of obesity and type 2 diabetes [52,53].
TG is produced by two biochemical pathways: the major glycerol phosphate pathway and the minor monoacylglycerol pathway. Diacylglycerol acyltransferase (DGAT) catalyzes acyl residue transfer from acyl-CoA to diacylglycerol (DAG), is considered the exclusive key enzyme for the final step required for both pathways as described by Cases et al. , Kennedy  and Yen et al. . Therefore, DGAT became an attractive target for the control of obesity and other related disorders such as type 2 diabetes .
Several benzimidazole derivatives was prepared and evaluated for their DGAT inhibitory activity using rat liver microsome. Furfurylamine containing benzimidazole carboxamide 23 was among the newly synthesized compounds which showed the most potent DGAT inhibitory effect (IC50=4.4 lM) and inhibited triglyceride formation in HepG2 cells. Furthermore, compound 23 reduced body weight gain in mice which are fed a high-fat diet. This was associated with decreased levels of triglyceride, cholesterol, and LDL-cholesterol in the blood accompanied with a significant increase in HDL-cholesterol level  (Scheme 10).
Carbonic anhydrases are zinc-containing metalloenzymes .
Several investigators identified fifteen carbonic anhydrase isoforms in humans which are located which possess different catalytic activity and subcellular localization [60-61]. Pastorekova et al.  and Supuran et al.  showed that these enzymesare involved in essential biochemical processes involving the hydration of carbon dioxide to bicarbonate and vice versa. Therefore these enzymes are involved in physiological processes such as lipogensis ,gluconeogenesis among other processes. Therefore, carbonic anhydrases are considered important targets for design of inhibitors with potential therapeutic applications. Aromatic/ heterocyclic sulfonamides are the most important class of CA inhibitors studied for the development of antiglaucoma, antitumor, antiobesity or anticonvulsant drugs [63,64].
Benzimidazo[1,2-c][1,2,3]thiadiazole-7-sulfonamides were synthesized and their binding to two carbonic anhydrase isozymes measured by isothermal titration calorimetry (ITC). The observed association constants between human carbonic anhydrase I (hCAI) and bovine carbonic anhydrase II (bCAII) and the inhibitors where in the range from 1.1 × 106 to 2. 6 × 107 M-1 respectively.
Compound 24 bound strongly to both isozymesof carbonic anhydrase with the observed Kd of about 0.04 lM. Compound 25 was the most specific binder of hCAI that bound about four fold stronger to hCAI than to bCAII while compound 26 bound threefold tighter to bCAII than to hCAI .
This review discusses several novel benzimidazole derivatives that possess antidiabetic activity.
Several agents demonstrated potential activities that they were marketed as useful agents for the treatment of type 2 diabetes operating on various mechanism(s) of actions. Efforts are still going on in the search of new benzimidazole derivatives that are pharmacologically effective and safe as antidiabetic agents [68-72].
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