Next Article in Journal
The Effects of Drying Techniques on Phytochemical Contents and Biological Activities on Selected Bamboo Leaves
Next Article in Special Issue
New Biologically Hybrid Pharmacophore Thiazolidinone-Based Indole Derivatives: Synthesis, In Vitro Αlpha-Amylase and Αlpha-Glucosidase Along with Molecular Docking Investigations
Previous Article in Journal
Microbial Degradation, Spectral analysis and Toxicological Assessment of Malachite Green Dye by Streptomyces exfoliatus
Previous Article in Special Issue
Phytochemical Composition, Antibacterial, Antioxidant and Antidiabetic Potentials of Cydonia oblonga Bark
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 27
Issue 19
10.3390/molecules27196457
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Synthesis of Novel Benzimidazole-Based Thiazole Derivatives as Multipotent Inhibitors of α-Amylase and α-Glucosidase: In Vitro Evaluation along with Molecular Docking Study

by
Rafaqat Hussain
1,
Shahid Iqbal
2,*,
Mazloom Shah
3,
Wajid Rehman
1,*,
Shoaib Khan
1,
Liaqat Rasheed
1,
Fazal Rahim
1,
Ayed A. Dera
4,
Sana Kehili
5,
Eslam B. Elkaeed
6,
Nasser S. Awwad
7,
Majed A. Bajaber
7,
Mohammed Issa Alahmdi
8,
Hamad Alrbyawi
9 and
Hashem O. Alsaab
10
1
Department of Chemistry, Hazara University, Mansehra 21300, Khyber Pakhtunkhwa, Pakistan
2
Department of Chemistry, School of Natural Sciences (SNS), National University of Science and Technology (NUST), H-12, Islamabad 46000, Pakistan
3
Department of Chemistry, Abbottabad University of Science and Technology (AUST), Abbottabad 22500, Pakistan
4
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha 61413, Saudi Arabia
5
Adham University College, Umm Al-Qura University, Makkah 21955, Saudi Arabia
6
Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh 13713, Saudi Arabia
7
Chemistry Department, Faculty of Science, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia
8
Department of Chemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia
9
Pharmaceutics and Pharmaceutical Technology Department, College of Pharmacy, Taibah University, Medina 42353, Saudi Arabia
10
Department of Pharmaceutics and Pharmaceutical Technology, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
*
Authors to whom correspondence should be addressed.
Molecules 2022, 27(19), 6457; https://doi.org/10.3390/molecules27196457
Submission received: 6 September 2022 / Revised: 26 September 2022 / Accepted: 27 September 2022 / Published: 30 September 2022
(This article belongs to the Special Issue Natural Products and Their Synthetic Scaffolds for Chronic Diseases: A Ray of Hope)
Browse Figures
Versions Notes

Abstract

:
In this study, hybrid analogs of benzimidazole containing a thiazole moiety (1–17) were afforded and then tested for their ability to inhibit α-amylase and α-glucosidase when compared to acarbose as a standard drug. The recently available analogs showed a wide variety of inhibitory potentials that ranged between 1.31 ± 0.05 and 38.60 ± 0.70 µM (against α-amylase) and between 2.71 ± 0.10 and 42.31 ± 0.70 µM (against α-glucosidase) under the positive control of acarbose (IC50 = 10.30 ± 0.20 µM against α-amylase) (IC50 = 9.80 ± 0.20 µM against α-glucosidase). A structure–activity relationship (SAR) study was carried out for all analogs based on substitution patterns around both rings B and C respectively. It was concluded from the SAR study that analogs bearing either substituent(s) of smaller size (−F and Cl) or substituent(s) capable of forming hydrogen bonding (−OH) with the catalytic residues of targeted enzymes enhanced the inhibitory potentials. Therefore, analogs 2 (bearing meta-fluoro substitution), 3 (having para-fluoro substitution) and 4 (with ortho-fluoro group) showed enhanced potency when evaluated against standard acarbose drug with IC50 values of 4.10 ± 0.10, 1.30 ± 0.05 and 1.90 ± 0.10 (against α-amylase) and 5.60 ± 0.10, 2.70 ± 0.10 and 2.90 ± 0.10 µM (against α-glucosidase), correspondingly. On the other hand, analogs bearing substituent(s) of either a bulky nature (−Br) or that are incapable of forming hydrogen bonds (−CH3) were found to lower the inhibitory potentials. In order to investigate the binding sites for synthetic analogs and how they interact with the active areas of both targeted enzymes, molecular docking studies were also conducted on the potent analogs. The results showed that these analogs adopted many important interactions with the active areas of enzymes. The precise structure of the newly synthesized compounds was confirmed using several spectroscopic techniques as NMR and HREI-MS.

1. Introduction

Hyperglycemia, which can be characterized as a high blood glucose level, describes the metabolic disorder known as diabetes mellitus (DM), which is non-infectious and chronic. The alarming incidence of diabetes mellitus already includes 415 million cases worldwide [1], and that figure is expected to rise to 642 million by 2040 [2,3]. Carbohydratesare hydrolyzed by the enzymes glucosidase and amylase to produce blood glucose. Inhibitors such α-glucosidase, which hydrolyze oligosaccharides into simple sugar, are secreted by the pancreas and salivary glands to decrease the absorption of glucose from the small intestine. The inhibitors of α-amylase and α-glucosidase delay the absorption of glucose, which lowers postprandial blood glucose levels and is thought to be a therapeutic strategy for the treatment of diabetes. Diabetes has been treated using a variety of methods, but the most popular strategy relies on blocking α-glucosidase and α-amylase, the carbohydrase enzymes that delay glucose absorption [4,5]. The α-amylase initiates the hydrolysis of maltodextrins, starch and maltooligosaccharide, which in turn releases glucose molecules [6,7]. Similar to α-amylase, the α-glucosidase enzyme catalyzes the hydrolytic reaction that releases glucose molecules from the carbohydrates [8,9]. Type-2 diabetes (T2DM) risk is decreased by inhibitors of α-amylase and α-glucosidase including acarbose, voglibose and miglitol. Oral diabetes medications offer a quick onset of action and strong therapeutic effects, but they can also cause negative side effects. The primary disadvantage is their manner of action, which typically lessens diabetic symptoms rather treating the pathophysiology of the condition as a whole. Therefore, exploring active compounds with low risk of side effects is important for treating T2DM [10,11,12].
Proton pump inhibitors, anti-histaminic, anti-convulsant, anti-analgesic, anti-coagulant, anti-hypertensive, anti-cancer, anti-fungal and antiviral are only a few of the biological properties that benzimidazole and its derivatives are known to exhibit [13,14,15,16,17,18,19]. Some pharmacologically bioactive drugs, including those of albendazole, benoxaprofen, astemizole, enviradine, omeprazole and bendamastin, have a benzimidazole component in their structural framework (Figure 1) [20].
The thiazole motif bearing scaffolds displayed a diverse range of biological profile including anti-bacterial, anti-diuretic and anti-Alzheimer’s [21]. Additionally, thiazole-based hybrid scaffolds find applications as biologically interesting scaffolds and were known to have promising pharmacological significance such as anti-microbial [22], anti-inflammatory, analgesic [23], anti-hypoxic profile [24], anticancer [25], anti-hypertensive [26] and anti-asthmatic [27] effects. Moreover, it was noted that numerous commercially available biologically active drugs, such as abafungin, ruvaconazole, azereonam and vorelaxin contain thiazole skeleton in their structures due to the wide spectrum of the pharmacological activities of the thiazole ring (Figure 2) [28,29].
Keeping in mind the biological significance of previously reported benzimidazole [30,31,32] and thiazole [33,34] analogs as α-amylase and α-glucosidase inhibitors for the treatment of diabetic patients, benzimidazole and thiazole rings were combined in the same molecules to find lead molecules in an effort to further enhance the α-amylase and α-glucosidase inhibitory potentials (Figure 3).

2. Results and Discussion

2.1. Chemistry

The preparation of benzimidazole-based thiazole derivatives (1–17) was completed in two steps. In the first step, 2-mercapto benzimidazole thiol (I) was treated with 4-nitro-substituted phenacyl bromide (II) in ethanol along with a catalytic amount of tri-ethyl amine under reflux condition to afford an intermediate (III) [35]. This intermediate was washed with petroleum ether in order to remove the impurities, and further this intermediate (III) was again reacted thiosemicarbazide and different substituted 2-bromoacetophenone via one-pot reaction in dioxane solvent and diethyl amine, and the subsequent residue was stirred under reflux for 8h to offer the synthesis of targeted benzimidazole-based thiazole derivatives (1–17). A thin-layer chromatographic (TLC) plate was used to monitor the conversion of reactants into products. All of the synthesized derivatives were purified by washing with petroleum ether and recrystallized from ethyl acetate to afford a purified form of the targeted benzimidazole-based thiazole analogs (1–17), which were then characterized through 1HNMR, 13CNMR and HREI-MS techniques (Scheme 1).
The precise structures of all newly afforded derivatives (1–17) were verified by NMR and HRMS. To better understand the spectral analysis of synthesized scaffolds (1–17), the synthesized compounds were divided into three major parts, including a benzimidazole part, a thiazole part and a 4-nitro benzene ring B and ring C respectively. The 1H-NMR results showed that protons of thiazole and benzimidazole (-NH) were resonated as a singlet at a chemical shift value of δH 7.28 and 12.55 ppm (for benzimidazole). In addition, a singlet was observed for the -NH proton present between benzimidazole and thiazole rings at δH11.98ppm. Besides that, the remaining protons of benzimidazole were recorded as multiplets at approximately δH 7.43–7.12 ppm, and the characteristic -S-CH2- groups between the benzimidazole and thiazole heterocyclic rings were observed at δH 3.782 ppm asa singlet. The remaining protons of ring C were resonated at approximately δH 7.36–8.35 ppm as multiplets (d, t, dt, dd), depending on the attached electron-withdrawing (EW) or electron-donating (ED) groups. In the 13C-NMR spectra, the typical shifts near δ13C 171.7 (C-thiazole), 155.6 (C=N), 150.2 (C-thiazole), 105.0 (CH-thiazole) and 37.5 (-S-CH2-) ppm reveal the presence of a thiazole ring, C=N and (-S-CH2-) moieties of the targeted benzimidazole-based thiazole analogs.

2.2. In Vitroα-Amylase and α-Glucosidase Inhibitory Activities (1–17)

All of the newly afforded benzimidazole-based thiazole analogs were tested for inhibitory activities against α-amylase and α-glucosidase and were illustrated to have moderate to good inhibition properties, having IC50 values ranging between 1.30 ± 0.05 to 38.60 ± 0.70 µM (against α-amylase) and 2.70 ± 0.10 to 42.30 ± 0.70 µM (α-glucosidase) when compared to standard acarbose (IC50 = 10.30 ± 0.20 µM for α-amylase) (IC50 = 9.80 ± 0.20 µM for α-glucosidase) (Table 1). Based on substitutions pattern around aryl part C, SAR studies were conducted for all synthesized derivatives, and the obtained results showed that each part of the synthesized analogs including benzimidazole ring A, the thiazole moiety and ring B and ring C are actively contributing in the activity of α-glucosidase and α-amylase, and any variation found in potency was owed to varying number(s),positions, and EW or ED natures of substituent(s)that are attached to aryl part C, respectively (Figure 4).

Structure–Activity Relationship (SAR) for Inhibitory Actions of α-Amylase and α-Glucosidase (1–17)

Analog 3 showed excellent potency among the synthesized series. By comparing analog 3bearing ortho-fluoro substitution on ring C along with a para-nitro group on ring B, with analogs 2 and 4 bearing a fluoro group at the meta- and ortho-positions of ring C; analog 3 displayed better activity toward α-amylase and α-glucosidase than its counterparts, 2 and 4. The difference in the inhibitory potentials of these three fluoro-substituted analogs toward α-amylase and α-glucosidase may be caused by different positions of the fluoro group around ring C (Table 1).
Analogs bearing chloro group(s) were found to display considerable inhibition against both these targeted enzymes (α-amylase and α-glucosidase). Among chloro-substituted analogs, analog 1 bearing di-Cl substitutions at the 3,4-position of the phenyl ring showed enhanced inhibitory potentials against both α-amylase and α-glucosidase enzymes when compared to other analogs, 14 (having a para-chloro group), 15 (bearing an ortho-chloro group) and 16 (with a meta-chloro group) bearing only one chloro group. This higher inhibitory potential of analog 1 might be due to greater numbers of attached chloro groups in comparison to other analogs 14, 15 and 16. However, analog 15 (IC50 = 5.20 ± 0.10 µM) bearing ortho-chloro substitution on the phenyl ring showed a superior activity for both alpha-amylase and alpha-glucosidase enzymes than its structurally similar counterparts 14 (IC50 = 16.40 ± 0.30 µM) and 16 (IC50 = 12.50 ± 0.20µM), demonstrating that altering the location of the substituent(s) around the phenyl ring has a significant impact on the inhibitory potentials (Table 1).
By comparing analog 10, bearing ortho-nitro substitution on phenyl ring C, with analogs 9 (having para-nitro substitution on ring C) and 17 (bearing meta-nitro substitution on ring C), analog 10exhibited better inhibitory potential than its structurally similar analogs 9 and 17. This suggests that the inhibitory potentials are increased by the nitro group’s ortho-position, which is more efficient for interactions with the active sites of both amylase and glucosidase enzymes. By moving the ortho-nitro group of ring C to its para-position, like in the case of analog 9, the inhibitory potential of analog 10 was drastically reduced. The potency was further decreased by shifting the ortho-nitro group to the meta-position as in analog 17. This difference in potency of these nitro-substituted analogs might be due to a different position of the nitro group around ring C (Table 1).
It was noteworthy that the attachment of substituent(s) of either a bulky nature (–Br group) or substituent(s) incapable of interactions through hydrogen bonding (-CH3 group) at various position of ring C along with the nitro-substitution at the 4-position of ring B resulted in decreased inhibitory potentials against both α-amylase and α-glucosidase. Therefore, analogs 6 (bearing para-bromo on ring C), 7 (having meta-bromo on ring C) and 8 (with an ortho-bromo moiety on ring C) showed many-fold less potency when compared to either chloro-substituted analogs 16 (meta-chloro-substitution on ring C), 14 (having para-chloro-substitution on ring C) and 15 (with ortho-chloro-substituted ring C) or fluoro-substituted analogs 2 (meta-fluoro-substitution on ring C), 3 (having para-fluoro-substituted on ring C) and 4 (with ortho-fluoro-substitution on ring C) respectively (Table 1).
On the basis of aforementioned observation, it was concluded that analogs bearing substituent(s) of smaller size was found to be a better competitor of both targeted α-amylase and α-glucosidase, compared to analogs that bear substituent(s) of larger size. Moreover, it was also noted that inhibition properties for both α-amylase and α-glucosidase enzymes were greatly influenced by varying the number(s), positions and natures (electron-donating or electron-withdrawing groups) of substituent(s) around both rings B and C, respectively.

2.3. Molecular Docking Study

Understanding how synthetic analogs interact with enzymes (both α-amylase and α-glucosidase) was the main goal of the molecular docking study. After using a command prompt, a docking procedure was completed, and nine different poses of each ligand was obtained in a log file in which the top-ranked conformations (having the lowest binding affinity) were selected in order to conduct a more complete visualization of protein–ligand interactions (PLI).
To explore the binding modalities of the ligand with the active site of the protein, a molecular docking study was carried out (Table 2). Varied software has been used to achieve the significant results; these software were Auto Dock Vina and discovery studio visualizer (DSV) [36,37,38,39]. α-Amylase and α-glucosidase protein were retrieved from an online source (https://www.rcsb.org/ (18 May 2022)). α-Amylase and α-glucosidase protein 1b2y and 3w37, respectively, were downloaded in PDB format. A different step procedure was adopted for the exploration of protein–ligand interactions (PLI). In the first step, the retrieved protein was opened in Auto Dock Vina; the water molecule was removed, and, in addition, polar hydrogen and Kollman and Gasteiger charges were added. This was followed by the addition of a ligand molecule wherein charges added, and coordinates for configuration (X, Y and Z) and the dimension of these coordinates were 80 and grid box center X = 25.555Å, Y = 61.538Å and Z = 51.515Å with exhaustiveness = 8. The saved file in text format and both protein and ligand were also saved in PDBQT format. 1b2y (chain-A, resolution = 3.20 Å, native ligand pyroglutamic acid and residue == 496 amino acid) and 3w37 (chain-A, resolution = 1.70 Å, native ligand acarbose and residue == 913 amino acid).
Interactions were discovered by using a command prompt in which the location of the target file was mentioned, and then processes were carried out. A total of nine poses for each ligand were obtained, which were explored in DSV to visualize binding interactions. A protein–ligand interaction (PLI) profile was summarized in (Figure 5, Figure 6 and Figure 7).

3. Experimental

3.1. General Information

The Bruker AM 500 MHz machine NMR was used for the characterization of new compounds, and all necessary chemicals and reagents were bought from Sigma Aldrich, St. Louis, MO, USA. The splitted pattern of the peak was recorded as follows: dt, doublet of triplets, dd, doublet of doublets; sextet; sext, quintet; quint, q, quartet; t, triplet; d, doublet; m, multiplet, s, singlet. The coupling constant (J) was measured in hertz (Hz). High-resolution electron impact mass spectra (HREI-MS) were recorded on a Finnigan MAT-311A mass spectrometer (Germany). On precoated silica gel aluminium plates, thin-layer chromatography (TLC) was carried out (Kieselgel 60254, E. Merck, Germany). TLC plates were visualized by a UV lamp with a wavelength of 254 and 365 nm; the melting point was recorded with a Buchi M-560.

3.2. General Method for the Production of Thiazole Scaffolds Based on Benzimidazole (1–17)

Initially, benzimidazole-2-thiol I (1 equivalent) was reacted and stirred with 4-nitro-substituted phenacyl bromide II (1 equivalent) in ethanol (10mL) and Et3N (a few drops) to afford the formation of substrate III [35]. In the next step, substrate III (1 equivalent), thiosemicarbazide (1 equivalent) and different substituted phenacyl bromide (1 equivalent) were reacted and refluxed in dioxane (10mL) and diethyl amine (1.5 equivalent) via a one-pot reaction. The residue was stirred for 8hrs under reflux. The solvent was evaporated on the completion of the reaction by employing reduced pressure to give a solid residue, which was further washed with petroleum ether and then recrystallized with ethyl acetate to access the formation of targeted benzimidazole-based thiazole derivatives (1–17) in appropriate yield. The precise structures of all of the newly synthesized derivatives were confirmed by using NMR and HREI-MS spectroscopic methods.
Appendix: 3.2. α-amylase inhibition assay, 3.2. α-glucosidase inhibition assay, 3.4. Doc king protocol [32] and 3.5. General procedures along with spectral analysis are provided in Supplementary Materials [40,41,42].

4. Conclusions

In conclusion, by employing acarbose as a standard drug, an approach was established for the synthesis of hybrid analogs of benzimidazole containing thiazole (1–17), which were then tested for their inhibition properties against α-amylase and α-glucosidase. All of the synthesized analogs were found to display a varied range of inhibition properties against both enzymes, with IC50 values of 1.31 ± 0.05 to 38.60 ± 0.70 µM (for α-amylase) and 2.71 ± 0.10 to 42.31 ± 0.70 µM (for α-glucosidase) when compared to standard acarbose (IC50 = 10.30 ± 0.20 µM for α-amylase) (IC50 = 9.80 ± 0.20µM for α-glucosidase). Among the synthesized series, seven analogs such as 1, 2, 3, 4, 5, 10 and 15 were found to be more potent than standard acarbose, with IC50 values of 2.20 ± 0.10, 4.10 ± 0.10, 1.30 ± 0.05, 1.90 ± 0.10, 3.60 ± 0.20, 7.20 ± 0.20 and 5.20 ± 0.10 (against α-amylase) and 3.90 ± 0.20, 5.60 ± 0.10, 2.70 ± 0.10, 2.90 ± 0.10, 4.30 ± 0.30, 9.60 ± 0.20 and 6.30 ± 0.10, respectively (against α-glucosidase). Besides that, the remaining ten analogs also exhibited considerable inhibitory potentials but were found to be less potent than standard acarbose. For active analogs, molecular docking was devised in order to examine the binding locations of synthetic analogs and how they interact with the catalytic cavity of amino acids in enzymes. The findings showed that these analogs adopted a number of significant interactions with the active regions of enzymes. In addition, various spectroscopic tools such as HREI-MS and NMR were employed to confirm the precise structure of the synthesized compounds.

Supplementary Materials

The following supporting information can be downloaded at: www.mdpi.com/article/10.3390/molecules27196457/s1, Supplementary Information file [40,41,42].

Author Contributions

Conceptualization, writing-original draft Preparation, R.H. and S.I.; methodology, M.S.; software, W.R.; validation, project administration, S.K. (Sana Kehili), L.R. and F.R.; writing review and editing, resources, funding, A.A.D., S.K. (Shoaib Khan) and E.B.E.; investigation, N.S.A.; resources, M.A.B.; data curation, M.I.A.; writing-original draft preparation, H.A. and H.O.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Deanship of Scientific Research at King Khalid University, Saudi Arabia, Grant number (RGP.2/167/43), the Deanship of Scientific Research at Umm Al-Qura University, Grant Code: (22UQU4340549DSR01) and Taif University Researchers Supporting Project number (TURSP-2020/67), Taif University, Taif, Saudi Arabia.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in Supplementary Materials.

Acknowledgments

The authors express their appreciation to the Deanship of Scientific Research at King Khalid University, Saudi Arabia, for funding this work through the research groups program under grant number RGP.2/167/43. The authors would like to thank the Deanship of Scientific Research at Umm Al-Qura University for supporting this work by Grant Code: (22UQU4340549DSR01), [email protected]. Hashem O. Alsaab would like to acknowledge Taif University Researchers Supporting Project number (TURSP-2020/67), Taif University, Taif, Saudi Arabia.

Conflicts of Interest

There are no conflicts to declare.

Sample Availability

Samples of the compounds are not available from the authors.

References

  1. Chen, L.; Magliano, D.J.; Zimmet, P.Z. The worldwide epidemiology of type 2 diabetes mellitus—Present and future perspectives. Nat. Rev. Endocrinol. 2012, 8, 228–236. [Google Scholar] [CrossRef]
  2. Munhoz, A.; Frode, T.S. Isolated compounds from natural products with potential antidiabetic activity—A systematic review. Curr. Diabetes Rev. 2018, 14, 36–106. [Google Scholar] [CrossRef] [PubMed]
  3. Kahn, S.E.; Cooper, M.E.; Del Prato, S. Pathophysiology and treatment of type 2 diabetes: Perspectives on the past, present, and future. Lancet 2014, 383, 1068–1083. [Google Scholar] [CrossRef]
  4. Taha, M.; Baharudin, M.S.; Ismail, N.H.; Selvaraj, M.; Salar, U.; Alkadi, K.A.; Khan, K.M. Synthesis and in silico studies of novel sulfonamides having oxadiazole ring: As ß-glucuronidase inhibitors. Bioorganic Chem. 2017, 71, 86–96. [Google Scholar] [CrossRef] [PubMed]
  5. Qaisar, M.N.; Chaudhary, B.A.; Sajid, M.U.; Hussain, N. Evaluation of a-glucosidase inhibitory activity of dichloromethane and methanol extracts of Croton bonplandianumbaill. Trop. J. Pharm. Res. 2014, 13, 1833–1836. [Google Scholar] [CrossRef]
  6. Tundis, R.; Loizzo, M.; Menichini, F. Natural products as a-amylase and aglucosidase inhibitors and their hypoglycaemic potential in the treatment of diabetes: An update. Mini Rev. Med. Chem. 2010, 10, 315–331. [Google Scholar] [CrossRef] [PubMed]
  7. Khan, M.; Alam, A.; Khan, K.M.; Salar, U.; Chigurupati, S.; Wadood, A.; Ali, F.; Mohammad, J.I.; Riaz, M.; Perveen, S. Flurbiprofen derivatives as novel a-amylase inhibitors: Biology-oriented drug synthesis (BIODS), in vitro, and in silico evaluation. Bioorganic Chem. 2018, 81, 157–167. [Google Scholar] [CrossRef]
  8. Okuyama, M.; Saburi, W.; Mori, H.; Kimura, A. a-glucosidases and a-1,4-glucan lyases: Structures, functions, and physiological actions. CellMol. Life Sci. 2016, 73, 2727–2751. [Google Scholar] [CrossRef]
  9. Taha, M.; Irshad, M.; Imran, S.; Chigurupati, S.; Selvaraj, M.; Rahim, F.; Ismail, N.H.; Nawaz, F.; Khan, K.M. Synthesis of piperazine sulfonamide analogs as diabetic-II inhibitors and their molecular docking study. Eur. J. Med. Chem. 2017, 141, 530–537. [Google Scholar] [CrossRef]
  10. Group, S.-N.T.R.; Chiasson, J.-L.; Josse, R.G.; Gomis, R.; Hanefeld, M.; Karasik, A.; Laakso, M. Acarbose for prevention of type 2 diabetes mellitus: The STOP-NIDDM randomised trial. Lancet 2002, 359, 2072–2077. [Google Scholar]
  11. Asgari, M.S.; Mohammadi-Khanaposhtani, M.; Kiani, M.; Ranjbar, P.R.; Zabihi, E.; Pourbagher, R.; Rahimi, R.; Faramarzi, M.A.; Biglar, M.; Larijani, B. Biscoumarin-1,2,3-triazole hybrids as novel anti-diabetic agents: Design, synthesis, in vitro aglucosidase inhibition, kinetic, and docking studies. Bioorganic Chem. 2019, 92, 103206. [Google Scholar] [CrossRef] [PubMed]
  12. Nissen, S.E.; Wolski, K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med. 2007, 356, 2457–2471. [Google Scholar] [CrossRef] [PubMed]
  13. Small, G.W.; Rabins, P.V.; Barry, P.P.; Buckholts, N.S.; Dekosky, S.T.; Ferris, S.H. Diagnosis and treatment of Alzheimer disease and related disorders. J. Am. Med. Assoc. 1997, 278, 1363–1371. [Google Scholar] [CrossRef]
  14. Spasov, A.; Yozhitsa, I.N.; Bugaeva, L.I.; Anisimova, V.A. Benzimidazole derivatives: Spectrum of pharmacological activity and toxicological properties (a review). Pharm. Chem. J. 1999, 33, 232–243. [Google Scholar] [CrossRef]
  15. Patil Ganguly, S.; Surana, S. A systematic review of benzimidazole derivatives as an antiulcer agent. Rasayan J Chem. 2008, 1, 447–460. [Google Scholar]
  16. Dubey, K.; Sanyal, P.K. Benzimidazoles in a wormy world. Vet Scan Online Vet. Med. J. 2010, 5, 63. [Google Scholar]
  17. Boiani, M.; González, M. Imidazole and benzimidazole derivatives as chemotherapeutic agents. Mini Rev. Med. Chem. 2005, 5, 409–424. [Google Scholar] [CrossRef]
  18. Narasimhan Sharma, D.; Kumar, P. Benzimidazole: A medicinally important heterocyclic moiety. Med. Chem. Res. 2012, 21, 269–283. [Google Scholar] [CrossRef]
  19. VishnuJi, R.; Arun, S.; Mahendra, N.; Ramendra, P. The Chemistry of Heterocycles: Nomenclature and Chemistry of Three-to-Five Membered Heterocycles; Elsevier: Amsterdam, The Netherlands, 2019; pp. 149–478. [Google Scholar]
  20. Bansal, Y.; Silakari, O.; Lapinsky, D.J.; Kusayanagi, T.; Tsukuda, S.; Shimura, S.; Manita, D.; Iwakiri, K.; Kamisuki, S.; Takakusagi, Y.; et al. The therapeutic journey of benzimidazoles: A review. Bioorganic Med. Chem. 2012, 20, 6208–6236. [Google Scholar] [CrossRef]
  21. Parekh, N.M.; Juddhawala, K.V.; Rawal, B.M. Antimicrobial activity of thiazolyl 3-benzenesulfonamide-condensed 2,4-thiazolidinediones derivatives. Med. Chem. Res. 2013, 22, 2737–2745. [Google Scholar] [CrossRef]
  22. Haroun, M.; Tratrat, C.; Tsolaki, E.; Geronikaki, A. Thiazole-Based Thiazolidinones as Potent Antimicrobial Agents. Design, Synthesis and Biological Evaluation. Comb. Chem. High Throughput Screen 2016, 19, 51–57. [Google Scholar] [CrossRef] [PubMed]
  23. Rostom, S.A.; El-Ashmawy, I.M.; Abd El Razik, H.A.; Badr, M.H.; Ashour, H.M. Design and Synthesis of Some Thiazolyl and Thiadiazolyl Derivatives of Antipyrine as Potential Non-Acidic Anti-Inflammatory, Analgesic and Antimicrobial Agents. BioorganicMed. Chem. 2009, 17, 882–895. [Google Scholar] [CrossRef]
  24. Zablotskaya, A.; Segal, I.; Germane, S.; Shestakova, I.; Domracheva, I.; Nesterova, A.; Geronikaki, A.; Lukevics, E. Silyl Modification of Biologically Active Compounds. 8. Trimethylsilyl Ethers of Hydroxyl-Containing Thiazole Derivatives. Chem. Heterocycl. Compd. 2002, 38, 859–866. [Google Scholar] [CrossRef]
  25. Luzina, E.L.; Popov, A.V. Synthesis and Anticancer Activity of N-Bis(Trifluoromethyl) Alkyl-N’-Thiazolyl and N-Bis(Trifluoromethyl)Alkyl-N’-BenzothiazolylUreas. Eur. J. Med. Chem. 2009, 44, 4944–4953. [Google Scholar] [CrossRef]
  26. Turan-Zitouni, G.; Chevallet, P.; Kilic, F.S.; Erol, K. Synthesis of Some ThiazolylPyrazoline Derivatives and Preliminary Investigation of Their Hypotensive Activity. Eur. J. Med. Chem. 2000, 35, 635–641. [Google Scholar] [CrossRef]
  27. Britschgi, M.; Greyerz, S.; Burkhart, C.; Pichler, W.J. Molecular Aspects of Drug Recognition by Specific T Cells. Curr. Drug Targets 2003, 4, 1–11. [Google Scholar] [CrossRef]
  28. Haroon, M.; Khalid, M.; Shahzadi, K.; Akhtar, T.; Saba, S.; Rafique, J.; Ali, S.; Irfan, M.; Alam, M.M.; Imran, M. Alkyl 2-(2-(arylidene) alkylhydrazinyl) thiazole-4-carboxylates: Synthesis, acetyl cholinesterase inhibition and docking studies. J. Mole. Struct. 2021, 1245, 131063. [Google Scholar] [CrossRef]
  29. Chhabria, M.; Patel, S.; Modi, P.; Brahmkshatriya, P. Thiazole: A review on chemistry, synthesis and therapeutic importance of its derivatives. Curr. Top. Med. Chem. 2016, 16, 2841–2862. [Google Scholar] [CrossRef] [PubMed]
  30. Hussain, S.; Taha, M.; Rahim, F.; Hayat, S.; Zaman, K.; Iqbal, N.; Selvaraj, M.; Sajid, M.; Bangesh, M.A.; Khan, F.; et al. Synthesis of benzimidazole derivatives as potent inhibitors for α-amylase and their molecular docking study in management of type-II diabetes. J. Mol. Struct. 2021, 1232, 130029. [Google Scholar] [CrossRef]
  31. Aroua, L.M.; Almuhaylan, H.R.; Alminderej, F.M.; Messaoudi, S.; Chigurupati, S.; Al-Mahmoud, S.; Mohammed, H.A. A facile approach synthesis of benzoylaryl benzimidazole as potential α-amylase and α-glucosidase inhibitor with antioxidant activity. Bioorganic Chem. 2021, 114, 105073. [Google Scholar] [CrossRef]
  32. Taha, M.; Rahim, F.; Zaman, K.; Selvaraj, M.; Uddin, N.; Farooq, R.K.; Nawaz, M.; Sajid, M.; Nawaz, F.; Ibrahim, M.; et al. Synthesis, α-glycosidase inhibitory potential and molecular docking study of benzimidazole derivatives. Bioorganic Chem. 2020, 95, 103555. [Google Scholar] [CrossRef] [PubMed]
  33. Rahim, F.; Tariq, S.; Taha, M.; Ullah, H.; Zaman, K.; Uddin, I.; Wadood, A.; Khan, A.A.; Rehman, A.U.; Uddin, N.; et al. New triazinoindole bearing thiazole/oxazole analogues: Synthesis, α-amylase inhibitory potential and molecular docking study. Bioorganic Chem. 2019, 92, 103284. [Google Scholar] [CrossRef] [PubMed]
  34. Taha, M.; Irshad, M.; Imran, S.; Rahim, F.; Selvaraj, M.; Almandil, N.B.; Mosaddik, A.; Chigurupati, S.; Nawaz, F.; Ismail, N.H.; et al. Thiazole based carbohydrazide derivatives as α-amylase inhibitor and their molecular docking study. Heteroat. Chem. 2019, 2019, 7502347. [Google Scholar] [CrossRef] [Green Version]
  35. Rahim, F.; Zaman, K.; Taha, M.; Ullah, H.; Ghufran, M.; Wadood, A.; Rehman, W.; Uddin, N.; Shah, S.A.A.; Sajid, M.; et al. Synthesis, in vitro alpha-glucosidase inhibitory potential of benzimidazole bearing bis-Schiff bases and their molecular docking study. Bioorganic Chem. 2020, 94, 103394. [Google Scholar] [CrossRef] [PubMed]
  36. Kharb, M.; Jat, R.K.; Parjapati, G.; Gupta, A. Introduction to molecular docking software technique in medicinal chemistry. Int. J. Drug Res. Technol. 2012, 2, 89–197. [Google Scholar]
  37. Li, Z.; Gu, J.; Zhuang, H.; Kang, L.; Zhao, X.; Guo, Q. Adaptive molecular docking method based on information entropy genetic algorithm. Appl. Soft Comput. 2015, 26, 299–302. [Google Scholar] [CrossRef]
  38. Rao, C.M.M.P.; Naidu, N.; Priya, J.; Rao, K.P.C.; Ranjith, K.; Shobha, S.; Chowdary, B.S.; Siddiraju, S. Molecular docking and dynamic simulations of benzimidazoles with beta-tubulins. Bioinformation 2021, 17, 404. [Google Scholar]
  39. Khan, S.; Ullah, H.; Rahim, F.; Nawaz, M.; Hussain, R.; Rasheed, L. Synthesis, in vitro α-amylase, α-glucosidase activities and molecular docking study of new benzimidazole bearing thiazolidinone derivatives. J. Mol. Struct. 2022, 1269, 133812. [Google Scholar] [CrossRef]
  40. Blum, C.; Roli, A.; Sampels, M. (Eds.) Hybrid Metaheuristics: An Emerging Approach to Optimization; Springer: Berlin, Germany, 2008; Volume 114. [Google Scholar]
  41. Baxter, J. Local optima avoidance in depot location. J. Oper. Res. Soc. 1981, 32, 815–819. [Google Scholar] [CrossRef]
  42. Azam, S.S.; Abbasi, S.W. Molecular docking studies for the identification of novel melatoninergic inhibitors for acetylserotonin-O-methyltransferase using different docking routines. Theor. Biol. Med. Model. 2013, 10, 63. [Google Scholar] [CrossRef] [Green Version]
Molecules 27 06457 g001 550
Figure 1. Benzimidazole skeleton containing drugs.
Figure 1. Benzimidazole skeleton containing drugs.
Molecules 27 06457 g001
Molecules 27 06457 g002 550
Figure 2. Biologically active drugs having a thiazole skeleton.
Figure 2. Biologically active drugs having a thiazole skeleton.
Molecules 27 06457 g002
Molecules 27 06457 g003 550
Figure 3. Rational of current study.
Figure 3. Rational of current study.
Molecules 27 06457 g003
Molecules 27 06457 sch001 550
Scheme 1. Preparation of hybrid analogs of thiazole incorporating a benzimidazole skeleton (1–17).
Scheme 1. Preparation of hybrid analogs of thiazole incorporating a benzimidazole skeleton (1–17).
Molecules 27 06457 sch001
Molecules 27 06457 g004 550
Figure 4. Summary of the structure–activity relationship (SAR) for inhibitory activities against α-amylase and α-glucosidase.
Figure 4. Summary of the structure–activity relationship (SAR) for inhibitory activities against α-amylase and α-glucosidase.
Molecules 27 06457 g004
Molecules 27 06457 g005 550
Figure 5. Representation of the protein–ligand interaction of compound 3. (A) For compound 3 against α-amylase, while (B) is for the same compound 3 against α-glucosidase.
Figure 5. Representation of the protein–ligand interaction of compound 3. (A) For compound 3 against α-amylase, while (B) is for the same compound 3 against α-glucosidase.
Molecules 27 06457 g005
Molecules 27 06457 g006 550
Figure 6. Representation of the protein–ligand interaction of compound 4. (A) For compound 4 against α-amylase, while (B) is for the same compound 4 against α-glucosidase.
Figure 6. Representation of the protein–ligand interaction of compound 4. (A) For compound 4 against α-amylase, while (B) is for the same compound 4 against α-glucosidase.
Molecules 27 06457 g006
Molecules 27 06457 g007 550
Figure 7. Representation of the protein–ligand interaction of compound 1. (A) For compound 1 against α-amylase, while (B) is for the same compound 1 against α-glucosidase.
Figure 7. Representation of the protein–ligand interaction of compound 1. (A) For compound 1 against α-amylase, while (B) is for the same compound 1 against α-glucosidase.
Molecules 27 06457 g007
Table
Table 1. The α-amylase and α-glucosidase inhibition properties (in vitro) by benzimidazole-containing thiazole analogs along with different substituent(s) (1–17).
Table 1. The α-amylase and α-glucosidase inhibition properties (in vitro) by benzimidazole-containing thiazole analogs along with different substituent(s) (1–17).
Synthesized
Compounds		Rα-Amylase
IC50 [µM]		α-Glucosidase
IC50 [µM]
13,4-dichloro2.20 ± 0.103.90 ± 0.20
23-fluoro4.10 ± 0.105.60 ± 0.10
34-fluoro1.30 ± 0.052.70 ± 0.10
42-fluoro1.90 ± 0.102.90 ± 0.10
54-hydroxy3.60 ± 0.204.30 ± 0.30
64-bromo18.50 ± 0.3025.80 ± 0.50
73-bromo34.70 ± 0.7036.40 ± 0.70
82-bromo20.30 ± 0.5029.30 ± 0.60
94-nitro16.40 ± 0.3019.60 ± 0.40
102-nitro7.20 ± 0.209.60 ± 0.20
114-methyl24.40 ± 0.3025.90 ± 0.40
123-methyl38.60 ± 0.7034.40 ± 0.70
132-methyl34.20 ± 0.6037.50 ± 0.70
144-chloro16.40 ± 0.3017.30 ± 0.30
152-chloro5.20 ± 0.106.30 ± 0.10
163-chloro12.50 ± 0.2013.60 ± 0.20
173-nitro28.40 ± 0.4029.60 ± 0.40
Standard acarbose drug10.30 ± 0.209.80 ± 0.20
Table
Table 2. The number(s) of hydrogen bond, IC50 values, binding energies, interacting residues and the closest residues of the selected docked analogs into the active site of both α-amylase and α-glucosidase enzymes.
Table 2. The number(s) of hydrogen bond, IC50 values, binding energies, interacting residues and the closest residues of the selected docked analogs into the active site of both α-amylase and α-glucosidase enzymes.
Active DerivativesName of EnzymeIC50
[µM]		Free Binding Energy (kcal/mol)Number of HBsNumber of Closest ResiduesInteracting Residues
3α-amylase1.30 ± 0.05−12.13117His305, Trp59, Ala198, Leu162, Lys200, His201 and Ile235
α-glucosidase2.70 ± 0.10−11.48216Phe476, Asp232, Trp432, Met470, Asp469, Arg552, Trp329 and Lys506
4α-amylase1.90 ± 0.10−10.87117Trp59, His201, Lys200, Ile235, Leu162, Ala198 and His305
α-glucosidase2.90 ± 0.10−10.19116Phe476, Ser505, Asn496, Lys506 and Arg552
1α-amylase2.20 ± 0.10−9.23117Tyr151, Lys200, His201, Ile235 and Gln63
α-glucosidase3.90 ± 0.20−8.98115Phe476, Ala 234, Ile233, Ala231, Asn496, Asp232 and Lys506
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Hussain, R.; Iqbal, S.; Shah, M.; Rehman, W.; Khan, S.; Rasheed, L.; Rahim, F.; Dera, A.A.; Kehili, S.; Elkaeed, E.B.; et al. Synthesis of Novel Benzimidazole-Based Thiazole Derivatives as Multipotent Inhibitors of α-Amylase and α-Glucosidase: In Vitro Evaluation along with Molecular Docking Study. Molecules 2022, 27, 6457. https://doi.org/10.3390/molecules27196457

AMA Style

Hussain R, Iqbal S, Shah M, Rehman W, Khan S, Rasheed L, Rahim F, Dera AA, Kehili S, Elkaeed EB, et al. Synthesis of Novel Benzimidazole-Based Thiazole Derivatives as Multipotent Inhibitors of α-Amylase and α-Glucosidase: In Vitro Evaluation along with Molecular Docking Study. Molecules. 2022; 27(19):6457. https://doi.org/10.3390/molecules27196457

Chicago/Turabian Style

Hussain, Rafaqat, Shahid Iqbal, Mazloom Shah, Wajid Rehman, Shoaib Khan, Liaqat Rasheed, Fazal Rahim, Ayed A. Dera, Sana Kehili, Eslam B. Elkaeed, and et al. 2022. "Synthesis of Novel Benzimidazole-Based Thiazole Derivatives as Multipotent Inhibitors of α-Amylase and α-Glucosidase: In Vitro Evaluation along with Molecular Docking Study" Molecules 27, no. 19: 6457. https://doi.org/10.3390/molecules27196457

APA Style

Hussain, R., Iqbal, S., Shah, M., Rehman, W., Khan, S., Rasheed, L., Rahim, F., Dera, A. A., Kehili, S., Elkaeed, E. B., Awwad, N. S., Bajaber, M. A., Alahmdi, M. I., Alrbyawi, H., & Alsaab, H. O. (2022). Synthesis of Novel Benzimidazole-Based Thiazole Derivatives as Multipotent Inhibitors of α-Amylase and α-Glucosidase: In Vitro Evaluation along with Molecular Docking Study. Molecules, 27(19), 6457. https://doi.org/10.3390/molecules27196457

Article Metrics

Back to TopTop