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. 2023 Mar 17;8(12):11433–11446. doi: 10.1021/acsomega.3c00265

Synthesis of Fluorinated Hydrazinylthiazole Derivatives: A Virtual and Experimental Approach to Diabetes Management

Hasnain Mehmood †, Tashfeen Akhtar †,*, Muhammad Haroon †,‡, Muhammad Khalid §,∥,*, Simon Woodward ⊥, Muhammad Adnan Asghar #, Rabia Baby ∇, Raha Orfali ○,*, Shagufta Perveen ◆
PMCID: PMC10061536  PMID: 37008089

Abstract

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A novel series of fluorophenyl-based thiazoles was synthesized following the Hanztsch method. All of the compounds were initially verified with physical parameters (color, melting point, retardation factor (Rf)), which were further confirmed by several spectroscopic methods, including ultraviolet–visible (UV–visible), Fourier-transform infrared (FTIR), 1H, 13C, 19F NMR, and high-resolution mass spectrometry (HRMS). The binding interactions of all compounds were studied using a molecular docking simulation approach. Furthermore, each compound was evaluated for its alpha(α)-amylase, antiglycation, and antioxidant potentials. The biocompatibility of all compounds was checked with an in vitro hemolytic assay. All synthesized scaffolds were found biocompatible with minimal lysis of human erythrocytes as compared to the standard Triton X-100. Among the tested compounds, the analogue 3h (IC50 = 5.14 ± 0.03 μM) was found to be a highly potent candidate against α-amylase as compared to the standard (acarbose, IC50 = 5.55 ± 0.06 μM). The compounds 3d, 3f, 3i, and 3k exhibited excellent antiglycation inhibition potential with their IC50 values far less than the standard amino guanidine (IC50 = 0.403 ± 0.001 mg/mL). The antidiabetic potential was further supported by docking studies. Docking studies revealed that all synthesized compounds exhibited various interactions along enzyme active sites (pi–pi, H-bonding, van der Waals) with varied binding energies.

Introduction

Halogen tagged compounds have diverse distributions in nature and have a wide range of biological activities.1−4 Besides natural distribution, synthetic halogen-substituted compounds hold a special place in medicinal chemistry. Their significance and regular use in medicinal chemistry is reinforced by the fact that, despite the COVID-19 pandemic, more than 20 drugs bearing halogen substituents have been approved by FDA for alternative clinical use (Figure 1).5,6

Figure 1.

Figure 1

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FDA-approved halogen-based drugs.

Due to the distinctive stability characteristics of halogens, lead optimization for drug development, frequently incorporates halogens within their core structures. Fluorine and chlorine are the most common substituents in this regard, as indicated in Figure 1. Thus, halo-organic variations are key frontiers of medicinal chemistry.7 Their characteristic “halogen bonding”8 renders their multitude of organic, inorganic, and biological systems.9−12 The directional and strength comparability of halogen bonding with the hydrogen bond has attracted the widespread attention of medicinal chemists in medicinal chemistry.13,14

Fluorinated compounds do not show similar electrostatic potential trends to the other halogens due to small size of the fluorine atom.12,15 Fluorine has weak ability to form halogen bonds, but its strong C–F bond facilitates tuning of the physicochemical properties and molecular conformations of the drug leads.16 These properties include change in pKa of neighboring functionalities,17 lipophilicity,18 enhanced membrane permeability,19 and reduced steric effect.20 The importance of fluorine in medicinal chemistry is further supported by the fact that 13 new drugs containing fluorine were approved by the FDA in 2022.21 Some representative examples of these are presented in Figure 2.

Figure 2.

Figure 2

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FDA-approved fluorine-containing drugs.

The biological applications of halogenated compounds are also enriched when thiazole and hydrazinyl functionalities are also incorporated into their structures. Halogens in combination with hydrazinyl and thiazole moieties possess versatile biological activities.22−28 Some important biological applications of halogenated hydrazinylthiazole compounds are shown in Figure 3.

Figure 3.

Figure 3

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Biologically active halogenated hydrazinylthiazole-based scaffolds.

Recently, Shahzadi et al. reported the antiglycation potential of alkyl-based hydrazinylthiazoles.29 Compounds I and II (Figure 4) were highlighted as excellent antiglycating agents with IC50 values of 1.848 ± 0.646 and 0.0004 ± 1.097 μM, respectively (amino guanidine, IC50= 25.50 ± 0.337 μM). In addition, Hasnain et al. reported the syntheses of two series of hydrazinylthiazoles and evaluated their antiglycation and α-amylase inhibition potential.30,31 Compounds III and IV (Figure 4) were found to be potential α-amylase inhibitors with IC50 values of 4.80 ± 0.07 and 4.79 ± 0.08 μM, respectively (acarbose, IC50 = 5.62 ± 0.04 μM). They also reported compound V as an excellent antiglycating agent with IC50 value of 0.383 ± 0.001 mg/mL as compared to the standard amino guanidine (IC50 = 0.394 ± 0.001 mg/mL). The nonclassical bioisosterism, antidiabetic properties of halogenated compounds,26,32−36 and in continuation of our research to explore thiazoles in search of an excellent antidiabetic agent guided us in structural planning of the proposed study (Figure 4).

Figure 4.

Figure 4

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Synthetic inspiration for the targeted antidiabetic agents.

Results and Discussion

To synthesize 2-(2-arylidenehydrazinyl)-4-(4-fluorophenyl)thiazoles (3a–o), an equimolar mixture of the respective thiosemicarbazones30,31 (1) and 2-bromo-4-fluoroacetophenone (2) was condensed together under reflux in ethanol for 4–5 h, as shown in Scheme 1. Cyclized products were achieved in moderate to good yields (61–80%).

Scheme 1. : Synthesis of 2-(2-Arylidenehydrazinyl)-4-(4-fluorophenyl)thiazoles (3a–o).

Scheme 1

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The formation of new compounds was clearly indicated by the change of physical parameters including color, melting points, and retardation factor (Rf) values. The structures of synthesized compounds were confirmed by spectroscopic studies (ultraviolet–visible (UV–visible), Fourier-transform infrared (FTIR), 1H, 13C and 19F NMR) and mass spectral data. In the IR spectra of the compounds, characteristic absorption bands in the region 3278–3138 cm–1 were seen due to N–H stretching. The absorption stretchings in the range 3151–2933 cm–1 were attributed to aliphatic C–H functionality. Azomethine (−CH=N−) linkage was indicated by the characteristic of C=N stretching in the range of 1699–1600 cm–1. Aromatic C=C stretching vibrations were observed in the region 1571–1436 cm–1. Characteristic thiazole vibrations were interpreted for the absorption bands in the region 1068–692 cm–1.37

In the 1H NMR spectra of the synthesized compounds, the N–H group appears in the range 11.26–12.50 ppm and one proton singlet at 7.85–8.43 ppm was ascribed to the azomethine protons. The thiazole proton present at position 5 of the ring was observed at 6.22–7.50 ppm. The signals of all other aromatic and aliphatic protons were observed in their expected regions with multiplicities corresponding to the required substitution pattern of the ring.

In the 19F NMR (proton-decoupled), one or two peaks corresponding to respective number of fluorine atoms present in the compounds were observed. For compounds 3d, 3g, 3i, 3k, and 3l, two signals were observed, indicating two fluorine atoms present in the structure, while the remaining monofluorinated compounds gave a single signal in the region −114.49 to −114.77 ppm.

In the 13C NMR spectra, signals of carbons at chemical shift values 168.3–170.6, 148.8–160.9, and 101.8–104.5 ppm were assigned to C2, C4, and C5 of the thiazole ring, respectively. The carbon of the azomethine linkage was indicated by a signal in the region 135.5–148.3 ppm. A characteristic doublet was observed for ipso carbons bonded with fluorine in the region 162.0–164.7 ppm with the coupling constant in the range of 244.3–249.4 (1JCF) Hz. Smaller doublets at 115.9–116.1 ppm were observed with the coupling constant 2JCF = 21.6 Hz. All other aromatic and aliphatic carbons were observed in their respective regions. The syntheses were further corroborated by high-resolution mass spectrometry (HRMS), where the calculated masses of synthesized compounds showed good agreement with the observed masses.

The synthesized compounds were assessed for their biological significance by evaluating the α-amylase, antiglycation, and antioxidant inhibition potentials. The cytotoxicity of all compounds was evaluated by in vitro hemolytic activity.

Biological Screening of 2-(2-Arylidenehydrazinyl)-4-(4-fluorophenyl)thiazoles (3a–o) α-Amylase Inhibition Activity

The compounds (3a–o) were evaluated for their enzyme inhibition potential against α-amylase, and the results are presented in Table 1. Acarbose was used as the standard (reference inhibitor) with an IC50 value of 5.55 ± 0.06 μM. All tested compounds exhibited enzyme inhibition potency from moderate to high with an effect of concentration. The IC50 values revealed that their inhibition potential is dose-dependent. The compound 3h (5-chloro-2-hydroxy) was found to be a more potent (IC50= 5.14 ± 0.03 μM) α-amylase inhibitor when compared with the standard. Besides 3h, the compound 3n (thiophen-2-yl, IC50= 5.77 ± 0.05 μM) showed good enzyme inhibition compared to the standard.

Table 1. Percentage α-Amylase Inhibition along with IC50 Values of Compounds 3a–o.

  % age α-amylase inhibition
  
compd. 1 μM 5 μM 10 μM IC50 ± SEM (μM)
3a 35.96 51.11 69.11 6.41 ± 0.09
3b 31.95 51.54 62.71 6.87 ± 0.01
3c 30.03 45.41 58.12 7.52 ± 0.05
3d 36.97 49.93 62.35 6.92 ± 0.12
3e 30.06 41.20 57.45 7.77 ± 0.01
3f 34.92 51.68 62.28 6.88 ± 0.16
3g 38.00 49.56 62.75 6.90 ± 0.23
3h 55.89 69.05 82.47 5.14 ± 0.03
3i 38.90 51.09 64.58 6.70 ± 0.08
3j 29.58 42.23 54.03 8.07 ± 0.12
3k 47.84 57.72 70.90 6.03 ± 0.04
3l 37.06 49.08 61.72 7.00 ± 0.13
3m 42.76 52.79 63.94 6.66 ± 0.13
3n 51.64 64.48 71.83 5.77 ± 0.05
3o 33.07 43.03 57.18 7.69 ± 0.18
acarbose 53.42 66.81 74.77 5.55 ± 0.06
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Similarly, the IC50 values of compounds 3b (2-bromo-4-methyl, IC50= 6.87 ± 0.01 μM) and 3f (3-bromo, IC50= 5.88 ± 0.16 μM) indicated that they also have almost comparable enzyme inhibition potential to the standard. The structure–activity relationship (SAR) studies revealed that the compound 3h, containing the −OH group, enhances the ability of the compound to form strong hydrogen bonding with the enzyme. The reason for exhibiting the comparable inhibition potential may be because of having the same substituent at different positions, which may be related to compounds 3d, 3i, and 3k showing a similar behavior.

Antiglycation Activity

The synthesized compounds (3a–o) were further evaluated for their antiglycation potential using amino guanidine as the reference inhibitor (IC50= 0.403 ± 0.001 mg/mL) as shown in Table 2. All compounds possess good to excellent antiglycation potential, with IC50 values ranging from 0.393 ± 0.002 to 0.584 ± 0.006 mg/mL.

Table 2. Percentage Antiglycation Inhibition along with IC50 Values of Compounds 3a–o.

  % age antiglycation inhibition
  
compd. 100 ppm 200 ppm 400 ppm 600 ppm 800 ppm 1000 ppm IC50 (mg ± SEM)
3a 80.912 82.097 84.808 85.864 86.983 89.880 0.410 ± 0.003
3b 81.189 84.602 85.170 86.200 86.768 87.462 0.413 ± 0.002
3c 67.583 68.855 69.669 75.722 77.932 81.626 0.464 ± 0.002
3d 87.417 87.923 89.045 89.475 90.859 92.275 0.394 ± 0.003
3e 68.735 69.659 70.703 71.831 72.794 73.677 0.493 ± 0.003
3f 84.146 86.734 87.272 87.994 90.418 91.338 0.399 ± 0.002
3g 24.260 34.557 48.804 54.331 66.643 74.646 0.584 ± 0.006
3h 50.878 56.497 65.488 68.424 68.964 70.744 0.528 ± 0.002
3i 87.964 88.535 89.110 89.990 91.164 92.228 0.393 ± 0.002
3j 52.257 61.537 66.470 70.267 76.184 79.161 0.488 ± 0.003
3k 87.393 87.943 88.776 89.221 89.978 91.580 0.396 ± 0.002
3l 79.853 81.769 83.050 84.648 86.160 87.099 0.418 ± 0.005
3m 76.769 78.789 82.499 83.963 86.080 88.774 0.418 ± 0.002
3n 79.297 80.987 82.086 83.014 85.776 87.827 0.420 ± 0.003
3o 83.693 84.223 85.521 86.434 88.18 89.496 0.407 ± 0.002
amino guanidine 85.190 86.141 87.143 88.011 88.866 89.657 0.403 ± 0.001
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An initial SAR was established for targeted compounds, which indicated that the inhibition potential depends upon the nature of the substituent and its position on the aromatic ring. Compound 3i exhibited the highest inhibition activity (IC50= 0.393 ± 0.002 mg/mL) having the trifluoromethyl group at position 3. Compounds 3d and 3k were also found to be more potent than the standard having IC50 values of 0.394 ± 0.003 and 0.396 ± 0.002 mg/mL, respectively. The comparable antiglycation potential of compounds 3d, 3i, and 3k is ascribed to the presence of the same substituent (trifluoromethyl) at positions 4, 3, and 2, respectively. The compound 3f bearing the bromine atom at position 3 also exhibited more antiglycation potential (IC50= 0.399 ± 0.002 mg/mL), compared to the standard. The IC50 values of all other tested compounds indicated that the inhibitory potential depends upon the substituent on the aromatic ring. The results also revealed that the percentage antiglycation is also dose-dependent; with an increase in concentration of the tested sample, the antiglycation activity increases.

SAR studies also revealed that the antiglycation activity is affected by the nature of groups present around the thiazole ring. While comparing our current results with previous studies, it may be concluded that the presence of 4-fluorophenyl functionality around the thiazole ring enhanced the glycation inhibition potential of the compounds. The argument may be strengthened by the current results, where 3k, 3i, and 3d showed enhanced antiglycation activity as compared to the standard (Figure 5).30,31

Figure 5.

Figure 5

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Antiglycation activity: structural comparison of our current work with previously reported work.

Free Radical Scavenging Ability (Antioxidant Activity)

The compounds 3a–o were screened for their DPPH free radical scavenging ability, and the results are presented in Table 3. Most compounds showed fairly good antioxidant potential but less active than the standard (IC50 = 7.18 ± 0.01 mM). The compound 3j, bearing the ethoxy group at position 2 of the arylidene ring, was found to be the most active in this series with an IC50 value of 8.33 ± 0.08 mM, almost comparable to that of the standard. The increased percentage antioxidant potential of the other compounds is as follows: 3o < 3n < 3l < 3a < 3c < 3b < 3d. The percentage antioxidant potential of the other compounds 3e, 3f, 3g, 3h, 3i, 3k, and 3m was less than 50%, so their IC50 values were not calculated. The results revealed that the percentage antioxidant potential is also dose-dependent. Most of the tested compounds at their lower concentration did not show significant activity but were found to be active when the concentration increases.

Table 3. Percentage Antioxidant Potential along with IC50 Values of Compounds 3a–oa.

  % age antioxidant potential
  
compd. 3 mM 6 mM 9 mM 12 mM 15 mM IC50 (mM ± SEM)
3a 0.00 18.82 32.72 47.58 67.95 12.39 ± 0.10
3b 8.77 23.69 36.38 53.65 69.82 11.32 ± 0.14
3c 0.00 11.13 34.28 57.51 73.34 11.43 ± 0.12
3d 23.48 34.45 45.32 56.39 63.78 10.68 ± 0.08
3e 0.00 8.26 19.32 44.74 49.04  
3f 0.00 0.00 19.48 28.70 40.73  
3g 0.00 0.00 0.00 0.00 8.45  
3h 0.00 0.00 0.00 8.78 23.25  
3i 0.00 8.64 18.87 32.26 46.53  
3j 18.18 45.90 62.07 75.45 78.51 8.33 ± 0.08
3k 0.00 14.08 21.05 30.92 48.28  
3l 0.00 15.62 32.06 46.14 65.18 12.94 ± 0.01
3m 0.00 0.00 0.00 15.13 31.05  
3n 0.00 12.72 30.39 45.47 59.36 13.86 ± 0.04
3o 0.00 7.68 18.22 30.15 53.73 17.97 ± 0.27
ascorbic acid 52.34 61.01 74.41 81.85 84.92 7.18 ± 0.01
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a

IC50 values: Concentration of the sample (mM) at which DPPH is scavenged by 50%.

In Vitro Hemolytic Activity

The compounds 3a–o were screened for their cytotoxicity behavior through a hemolytic assay, and the results are presented in Table 4. The compounds 3b, 3c, 3f, 3j, and 3l were found safe at their minimum treated concentration (10 μM), while all other compounds were found to be fatal to red blood cells and caused lysis of RBCs at all tested concentrations. The percentage hemolysis is also found to be dose-dependent; lysis increases when the concentration of the sample increases.

Table 4. Percentage Hemolysis of Compounds 3a–o.

  % hemolysis
compd. 10 μM 50 μM 100 μM
3a 3.06 15.10 32.23
3b 0.00 7.90 31.56
3c 0.00 8.38 32.09
3d 16.05 25.71 40.97
3e 1.20 11.50 40.38
3f 0.00 15.57 40.19
3g 1.98 26.35 52.27
3h 3.11 21.17 52.50
3i 14.70 30.72 44.54
3j 0.00 16.83 32.47
3k 4.43 27.62 45.69
3l 0.00 19.99 36.64
3m 2.58 26.29 46.22
3n 11.42 32.43 61.41
3o 1.99 21.55 49.12
triton X-100 100 100 100
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Molecular Docking

The compounds 3a–o were virtually screened against two proteins, i.e., human serum albumin (HSA) and human pancreatic α-amylase (HPA), by molecular docking. HSA is a carrier protein that also serves as a marker for uncontrolled diabetes. This protein becomes heavily glycated due to long-term elevated glucose levels.38 The protein glycation may contribute to oxidative stress and inflammation. Here, we have performed antiglycation studies for the synthesized ligands (3a–o) using the HSA three-dimensional structure as a target protein. HAS has multiple glycation sites (F1–9) in its three domains.39,40 Sudlow site II is a fatty acid binding site mainly consisting of Leu115, Pro118, Met123, Ala126, Phe134, Lys137, Tyr138, Glu141, Ile142, His146, Phe149, Leu154, Phe157, Tyr161, Leu185, Arg186, Gly189, Lys190, and Ser193 amino acids. The ligand 3a shows binding to the same Sudlow site II with a binding energy of −9.54 kcal/mol and a binding constant of 102 nM (Table 5). In the same site, two lysines and one histidine amino acid, i.e., Lys137, His146, and Lys190, constitute a major glycation site (FA1) in domain IB.41 The ligands 3(d, f, i, and k) share the same binding site involving Lys137, Leu115, Arg117, Met123, Ala126, Phe127, Asp129, Asn130, Thr133, Phe134, Lys137, Tyr138, Glu141, Ile142, Tyr161, Phe165, and Leu182 residues (Figure 6). These ligands form π–π stacking interactions with Tyr138 and show interactions with Lys137, one of the main residues that undergo glycation.42 Tyr138 and Tyr161 have previously been reported to interact with macrocycle rings of various drugs by π–π stacking,43 while Tyr161 and His146 are involved in the heme–Fe atom coordination; any ligand binding to these sites may disrupt heme–Fe interactions.41 Among these ligands, 3f shows a binding energy of −9.22 kcal/mol and a dissociation constant of 173 nM (Table 5). Although 3h shows a binding constant of 223 nM and a binding energy of −9.07 kcal/mol, it binds to a shared region of Sudlow sites I and II comprising residues, i.e., Ala191, Lys195, Leu198, Lys199, Ser202, Ala210, Phe211, Trp214, Lys436, Pro447, Cys448, Ala449, Asp451, Tyr452, Val455, and Leu481. This binding site includes a part of Sudlow site I, where Lys199 is responsible for 5% of the total glycation.44,45In vitro results also corroborate the best IC50 obtained with the same ligands exhibiting the highest binding energy in the in silico studies. Previously, triazole-based Schiff bases and thiazole-based thiosemicarbazones had shown antiglycation activities by in silico studies.46

Table 5. In Silico Antiglycation Activity with Binding Energy and Dissociation Constant of All Compounds 3a–o.

ligands binding energy (kcal/mol) dissociation constant (nM) active site
3a –9.54 102.28 Leu115, Pro118, Met123, Ala126, Phe134, Lys137, Tyr138, Glu141, Ile142, His146, Phe149, Leu154, Phe157, Tyr161, Leu185, Arg186, Gly189, Lys190, Ser193.
3b –8.64 465.05 Leu115, Met123, Ala126, Phe127, Asp129, Asn130, Thr133, Phe134, Lys137, Tyr138, Glu141, Ile142, Tyr161.
3c –9.09 216.92 Leu115, Val116, Arg117, Pro118, Met123, Phe134, Lys137, Tyr138, Glu141, Ile142, His146, Phe149, Phe157, Tyr161, Phe165, Leu182, Leu185, Arg186, Gly189, Lys190.
3d –8.53 557.19 Leu115, Met123, Ala126, Phe127, Asp129, Asn130, Glu131, Thr133, Phe134, Lys137, Tyr138, Glu141, Ile142, Tyr161.
3e –8.64 462.69 Leu115, Met123, Ala126, Phe127, Asp129, Asn130, Glu131, Thr133, Phe134, Lys137, Tyr138, Glu141, Ile142, Tyr161.
3f –9.22 173.72 Leu115, Pro118, Met123, Phe134, Lys137, Tyr138, Glu141, Ile142, His146, Tyr161, Leu182, Leu185, Arg186, Gly189, Lys190.
3g –8.7 421.72 Leu115, Pro118, Met123, Phe134, Lys137, Tyr138, Glu141, Ile142, His146, Phe149, Tyr161, Leu182, Leu185, Arg186, Gly189, Lys190.
3h –9.07 223.24 Ala191, Lys195, Leu198, Lys199, Ser202, Ala210, Phe211, Trp214, Lys436, Pro447, Cys448, Ala449, Asp451, Tyr452, Val455, Leu481.
3i –8.65 457.99 Leu115, Arg117, Met123, Ala126, Phe127, Asp129, Asn130, Thr133, Phe134, Lys137, Tyr138, Glu141, Ile142, Tyr161, Leu182.
3j –8.62 484.08 Leu115, Arg117, Met123, Ala126, Phe127, Asp129, Asn130, Thr133, Phe134, Lys137, Tyr138, Glu141, Ile142, Tyr161, Phe165, Leu182.
3k –8.53 560.99 Leu115, Arg117, Met123, Ala126, Phe127, Asp129, Asn130, Thr133, Phe134, Lys137, Tyr138, Glu141, Ile142, Tyr161, Phe165, Leu182.
3l –9.1 212.44 Leu115, Arg117, Met123, Lys137, Tyr138, Glu141, Ile142, His146, Phe149, Leu154, Phe157, Tyr161, Phe165, Leu182, Leu185, Arg186, Gly189, Lys190, Ser193.
3m –8.33 786.45 Leu115, Met123, Ala126, Phe127, Asp129, Asn130, Glu131, Thr133, Phe134, Lys137, Tyr138, Glu141, Ile142, Tyr161.
3n –8.19 1000.00 Leu115, Met123, Ala126, Phe127, Asp129, Asn130, Thr133, Phe134, Lys137, Tyr138, Glu141, Ile142, Tyr161.
3o –8.51 578.33 Leu115, Arg117, Met123, Ala126, Phe127, Asp129, Asn130, Thr133, Phe134, Lys137, Tyr138, Glu141, Ile142, Tyr161, Phe165, Leu182.
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Figure 6.

Figure 6

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Best docking interactions are shown by ligands 3a and 3h with binding energies of −8.78 and −8.26 kj/mol against human pancreatic α-amylase (HPA).

Human pancreatic α-amylase (HPA) has multiple ligand binding sites in its three-domain structure.47,48 Ligands 3a–o have been found to interact in four of these sites, with the binding energies ranging from −8.78 to −7.22 kcal/mol (Table 6). In HPA, Trp,59 Asp197, and Glu233 are the main catalytic site amino acids that interact with α-amylase inhibitors via π–π stacking, van der Waals, and H-bonding interactions, respectively. Many natural and synthetic compounds have been found to interact with active site residues (Trp59, Asp197, and Glu233) in HPA.49−51 In our study, most of the ligands, i.e., 3(a, c, e, i–o), were found to interact with these active site residues (Figure 7). The ligand 3a was found to be a better α-amylase inhibitor. It interacts with all three domains of HPA while binding at four different sites (Figure 7). The ligand 3a shows the best binding energy (−8.59 kcal/mol) with a dissociation constant of ∼506 nM when interacting with the C-terminal domain (Domain III) and −7.94 kcal/mol of binding energy with 1.5 μM dissociation constant when binding to the main active site of the enzyme (Table 6). The active site residues include Trp58, Trp59, Tyr62, Gln63, His101, Gly104, Asn105, Ala106, Val107, Leu162, Thr163, Gly164, Leu165, Arg195, Asp197, Ala198, Glu233, His299, and Asp300 (Figure 7). Here, Ala,105,106 Gln63, and Arg195 are found to interact via H-bonding. In silico findings for ligand 3n agree with the in vitro results. It interacts proximate to the active site residues with a binding energy of −8.31 kcal/mol and a dissociation constant of 8.1 μM (Table 6). The ligand 3h, which has been found to be the best α-amylase inhibitor in experimental IC50, interacts proximate to N- and C-terminal domains and does not directly disrupt the enzyme active site (Figure 7). The ligand 3k interacts with active site residues (Trp59, Glu60, Tyr62, Gln63, His101, Tyr151, Leu162, Thr163, Leu165, Asp197, Ala198, Ser199, Lys200, His201, Glu233, Val234, Ile235) as well as domain III (C-terminal) of the enzyme with binding energies of -7.76 and -7.71 kcal/mol with dissociation constants of 2.06 and 2.23 μM (Table 6). The ligand 3k also showed an IC50 of 6.03 ± 0.04 μM in in vitro amylase inhibition (Table 1). Previously, some α-amylase inhibitors were found to form hydrogen bonds with Ile235 and Glu233 and charge−π interactions with His151. In our findings, His101 and His201 have been found to interact with 3a–o ligands via charge−π and π–π interactions.

Table 6. In Silico α-Amylase Inhibition Potential with Binding Energy and Dissociation Constant of All Compounds 3a–o.

ligands binding energy (kcal/mol) dissociation constant (μM) active site
3a –8.78 0.36 Tyr2, Ser3, Asn5, Thr6, Gln7, Gln8, Arg92, Leu217, Trp221, Phe222, Pro223, Gly225, Ser226, Lys227, Pro228, Phe229, Ile230.
3a –8.59 0.51 Asp451, Ile453, Ser454, Ile465, Lys466, Ile467, Tyr468, Ala475, His476, Phe477, Ser478, Ile479, Ser480, Ala483, Glu484, Asp485, Phe487, Ile488.
3a –7.94 1.52 Trp58, Trp59, Tyr62, Gln63, His101, Gly104, Asn105, Ala106, Val107, Leu162, Thr163, Gly164, Leu165, Arg195, Asp197, Ala198, Glu233, His299, Asp300.
3a –7.89 1.64 Tyr67, Lys68, Leu69, Cys70, Asn75, Glu76, Asp77, Cys115, Lys178, Glu181, Tyr182, His185, Leu186.
3b –7.91 1.6 Thr439, Ile465, Lys466, Ile467, Tyr468, Ser470, Asp472, Lys474, Ala475, His476, Phe477, Ser478, Ile488.
3b –7.74 2.12 Arg267, Gln302, Arg303, Gly304, His305, Ala310, Ile312, Thr314, Trp316, Asp317, Arg346, Phe348, Gly351, Asn352, Asp353, Val354, Asp356.
3c –8.1 1.16 Trp59, Tyr62, Gln63, His101, Tyr151, Leu162, Thr163, Leu165, Arg195, Asp197, Ala198, Ser199, Lys200, His201, Glu233, Val234, Ile235.
3c –7.62 2.59 Arg389, Gln390, Asp451, Ile453, Ser454, Ile465, Lys466, Ile467, Tyr468, His476, Phe477, Ser478, Ile479, Ser480, Ala483, Glu484, Asp485, Pro486, Phe487, Ile488.
3d –7.61 2.65 Tyr67, Lys68, Leu69, Cys70, Asn75, Glu76, Asp77, Cys115, Ala128, Val129, Lys178, Glu181, Tyr182, His185.
3e –7.3 4.44 Tyr 67, Lys 68, Leu 69, Cys 70, Asn 75, Glu 76, Asp 77, Cys 115, Ala 128, Val 129, Lys 178, Glu 181, Tyr 182, His 185
3e –7.22 5.07 Arg 389, Gln 390, Ser 435, Phe 436, Ser 437, Asp 451, Ile 453, Ser 454, Ile 465, Ser 478, Ile 479, Ser 480, Ala 483, Glu 484, Asp 485, Pro 486, Phe 487, Ile 488
3f –7.83 1.83 Arg 389, Ser 435, Phe 436, Ser 437, Asp 451, Ile 453, Ser 454, Ile 465, Ser 478, Ile 479, Ser 480, Ala 483, Glu 484, Asp 485, Pro 486, Phe 487, Ile 488
3f –7.78 2.00 Ser 66, Tyr 67, Lys 68, Leu 69, Cys 70, Asn 75, Glu 76, Asp 77, Cys 115, Ala 128, Val 129, Glu 181, Tyr 182, His 185
3g –7.42 3.66 Arg 389, Gln 390, Ser 435, Phe 436, Ser 437, Asp 451, Ile 453, Ser 454, Ile 465, Ser 478, Ile 479, Ser 480, Ala 483, Glu 484, Asp 485, Pro 486, Phe 487, Ile 488
3h –8.26 0.88 Tyr 67, Lys 68, Leu 69, Cys 70, Asn 75, Glu 76, Asp 77, Cys 115, Ala 128, Val 129, Lys 178, Glu 181, Tyr 182, His 185
3h –8.18 1.01 Thr 439, Ile 465, Lys 466, Ile 467, Tyr 468, Ser 470, Lys 474, Ala 475, His 476, Phe 477, Ser 478, Ile 488
3i –7.99 1.40 Ser 66, Tyr 67, Lys 68, Leu 69, Cys 70, Asn 75, Glu 76, Asp 77, Cys 115, Ala 128, Val 129, Glu 181, Tyr 182, His 185
3j –7.74 2.12 Asp 451, Ile 453, Ser 454, Ile 465, Lys 466, Ile 467, Tyr 468, Ala 475, His 476, Phe 477, Ser 478, Ile 479, Ser 480, Ala 483, Glu 484, Asp 485, Pro 486, Phe 487, Ile 488
3j –7.51 3.11 Trp 59, Glu 60, Tyr 62, Gln 63, His 101, Tyr 151, Leu 162, Thr 163, Leu 165, Asp 197, Ala 198, Ser 199, Lys 200, His 201, Glu 233, Val 234, Ile 235
3k –7.76 2.06 Trp 59, Glu 60, Tyr 62, Gln 63, His 101, Tyr 151, Leu 162, Thr 163, Leu 165, Asp 197, Ala 198, Ser 199, Lys 200, His 201, Glu 233, Val 234, Ile 235
3k –7.71 2.23 Thr 439, Ile 465, Lys 466, Ile 467, Tyr 468, Ser 470, Asp 472, Lys 474, Ala 475, His 476, Phe 477, Ser 478, Ile 488
3l –8.31 0.80 Trp 58, Trp 59, Tyr 62, His 101, Tyr 151, Leu 162, Leu 165, Arg 195, Asp 197, Ala 198, Ser 199, Lys 200, His 201, Glu 233, Val 234, Ile 235, Glu 240, Asn 298, His 299, Asp 300
3m –7.61 2.65 Arg 267, Gln 302, Arg 303, Gly 304, His 305, Ala 310, Ile 312, Thr 314, Trp 316, Asp 317, Arg 346, Phe 348, Gly 351, Asn 352, Asp 353, Val 354, Asp 356
3m –7.32 4.31 TRP 59, TYR 62, GLN 63, VAL 98, HIS 101, LEU 162, LEU 165, ASP 197, ALA 198, SER 199, LYS 200, HIS 201, GLU 233, VAL 234, ILE 235
3n –7.38 3.88 TRP 59, GLU 60, TYR 62, GLN 63, VAL 98, HIS 101, LEU 162, LEU 165, ASP 197, ALA 198, SER 199, LYS 200, HIS 201, GLU 233, VAL 234, ILE 235
3n –7.1 6.29 TYR 67, LYS 68, LEU 69, CYS 70, ASN 75, GLU 76, ASP 77, CYS 115, VAL 129, LYS 178, GLU 181, TYR 182, HIS 185
3o –7.67 2.40 ASP 451, ILE 453, SER 454, ILE 465, LYS 466, ILE 467, TYR 468, ALA 475, HIS 476, PHE 477, SER 478, ILE 479, SER 480, ALA 483, GLU 484, ASP 485, PHE 487, ILE 488
3o –7.65 2.46 TRP 59, GLU 60, TYR 62, GLN 63, HIS 101, TYR 151, LEU 162, THR 163, LEU 165, ASP 197, ALA 198, SER 199, LYS 200, HIS 201, GLU 233, VAL 234, ILE 235
3o –7.52 3.05 SER 66, TYR 67, LYS 68, LEU 69, CYS 70, ASN 75, GLU 76, ASP 77, CYS 115, ALA 128, VAL 129, LYS 178, GLU 181, TYR 182, HIS 185
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Figure 7.

Figure 7

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Best docking interactions are shown by ligands 3a and 3f with binding energies of −9.54 and −9.22 kj/mol against human serum albumin (HSA).

Conclusions

The current study was carried out for the synthesis of fluorophenyl-based hydrazinylthiazole derivatives. 15 compounds were synthesized through a two-step synthetic protocol, and the majority of the compounds were obtained in good yields. The verification of formation and confirmation of the proposed skeleton of all synthesized scaffolds was achieved with spectroscopic techniques (UV–visible, FTIR, 1H, 13C, 19F NMR, HRMS). Biological screening of all synthesized compounds was carried out against α-amylase, glycation, and oxidation processes. The synthesized compounds showed comparable with standard to excellent activities. The compound 3h was found to be an excellent α-amylase inhibitor. The compounds 3d, 3f, 3i, and 3k showed the highest potency for the glycation inhibition process. All synthesized scaffolds were found biocompatible in nature due to minimal lysis of human erythrocytes as compared to the standard Triton X-100. All synthesized compounds exhibited various interactions along enzyme active sites (pi–pi, H-bonding, van der Waals) with varied binding energies evaluated through a molecular docking study.

Experimental Section

Materials and Methods

All reagents and solvents used in syntheses of compounds 3a–o were of analytical grade and used as received without further purification. The reagents and solvents were purchased from commercial sources (Sigma-Aldrich Merck, Fischer, and Acros Organics). Precoated thin-layer chromatographic aluminum sheets (Kiesel gel 60, F254, E. Merck, Germany) were used to monitor the progress and purity of synthesized compounds. Melting points (M.p.) were recorded in open capillaries using a DMP-300 A&E Lab, U.K., melting point apparatus and are uncorrected. Ultraviolet (UV) absorption spectra were recorded on a Shimadzu Ultraviolet-1800 spectrophotometer in DMSO. IR spectra were recorded on a Bruker OPUS using attenuated total reflectance (ATR) to identify the functional groups. Proton (1H), carbon (13C), and fluorine (19F) NMR experiments were performed on Bruker DPX-400 and 500 MHz spectrometers. Mass spectra were recorded on the Bruker Micro time of flight-electrospray ionization (TOF-ESI) positive targeted mode. Fluorescence of glycated products was measured on a Shimadzu RF-6000 spectrofluorometer.

General Procedure for the Syntheses of 2-(2-Arylidenehydrazinyl)-4-(4-fluorophenyl)thiazoles (3a–o)

The synthesis of 3a–o was achieved by the Hantzsch thiazole synthetic protocol. Respective aryl-substituted thiosemicarbzones30,31 (0.001 mol) and 2-bromo-4-fluoroacetophenone (0.001 mol) in absolute ethanol were heated under reflux for 4–5 h. Reaction progress and completion were indicated by TLC, measured at regular intervals. Appearance of a single spot on the TLC plate highlighted the completion of reaction. Upon completion, the reaction mixture was allowed to attain room temperature for 30 min. The reaction mixture was then poured on crushed ice, which resulted in precipitation of the solid. The resulting precipitated solid was filtered through suction. The obtained solid was washed with plenty of water to remove the mother liquor. The formed solid was dried under vacuum to obtain the pure product. The NMR spectra (400 MHz) of 3a–o were recorded in DMSOd6 except for 3a, 3c, and 3d, which were run in chloroform CDCl3.

2-(2-(2-Bromo-4,5-dimethoxybenzylidene)hydrazinyl)-4-(4-fluorophenyl)thiazole (3a)

Brick-red solid; yield: 79%; M.p.: 213–215 °C; Rf: 0.44 (acetone/n-hexane, 1:3); λmax = 283, 357 nm; FTIR (ATR) cm–1: 3057 (=C–H stretching), 2937 (C–H aliphatic stretching), 1693 (C=N stretching), 1595 (thiazole skeletal vibrations), 1504, 1436 (C=C aromatic ring stretchings), 1305 (C–H aliphatic bending), 1093 (C–O stretching), 1024–731 (characteristic thiazole vibrations); 1H NMR (400 MHz): δ (ppm) 8.29 (s, 1H, H–C=N−), 7.80 (dd, 2H, Ar–H, J = 9.0, 5.2 Hz), 7.49 (s, 1H, Ar–H), 7.19–7.13 (m, 2H, Ar–H), 7.03 (s, 1H, thiazole-H), 6.78 (s, 1H, Ar–H), 3.98 (s, 3H, −OCH3), 3.94 (s, 3H, −OCH3); 19F NMR (375 MHz): δ (ppm) −114.53; 13C NMR (100 MHz): δ (ppm) 168.7 (thiazole ring C2), 162.9(d, 1JCF = 248.3 Hz, Aripso), 151.3 (Ar–C–O–Me), 148.8 (thiazole ring C4), 148.2, 142.7 (H–C=N−), 129.3, 127.7 (d, 3JCF = 8.4 Hz, Ar), 124.9, 115.9 (d, 2JCF = 21.6 Hz, Ar), 115.3 (d, 2JCF = 26.0 Hz, Ar), 108.7 (Ar–C), 102.5 (thiazole ring C5), 56.3 (−OCH3), 56.0 (−OCH3); HRMS: m/z calculated for C18H15BrFN3O2S, [M + H]+: calcd: 436.0130, found: 436.0123; [M + Na]+: calculated: 457.9950, found: 457.9934; [2M + Na]+: calculated: 893.0002, found: 892.9978.

2-(2-(2-Bromo-4-methylbenzylidene)hydrazinyl)-4-(4-fluorophenyl)thiazole (3b)

Light-yellow solid; yield: 80%; M.p.: 190–192 °C; Rf: 0.49 (acetone/n-hexane, 1:3); λmax = 270, 357 nm; FTIR (ATR) cm–1: 3192 (N–H stretching), 2974 (C–H aliphatic stretching), 1600 (C=N stretching), 1489 (thiazole skeletal vibrations), 1436 (C=C aromatic ring stretchings), 1039–837 (characteristic thiazole vibrations); 1H NMR (400 MHz): δ (ppm) 12.35 (s, 1H, H–N−), 8.34 (s, 1H, H–C=N−), 7.89 (dd, 2H, Ar–H, J = 9.0, 5.6 Hz), 7.79 (d, 1H, Ar–H, J = 8.0 Hz), 7.50 (s, 1H, thiazole-H), 7.32 (s, 1H, Ar–H), 7.28–7.21 (m, 3H, Ar–H), 2.32 (s, 3H, −CH3); 19F NMR (375 MHz): δ (ppm) −114.57; 13C NMR (100 MHz): δ (ppm) 168.5 (thiazole ring C2), 162.1 (d, 1JCF = 248.3 Hz, Aripso), 150.0 (thiazole ring C4), 141.6 (H–C=N−), 140.0 (Ar–C–CH3), 133.7, 131.7, 130.8, 129.4, 127.9 (d, 3JCF = 8.1 Hz, Ar–C), 126.7, 122.9, 115.9 (d, 2JCF = 21.6 Hz, Ar–C), 104.1 (thiazole ring C5), 20.9 (−CH3); HRMS: m/z calculated for C17H13BrFN3S, [M + H]+: calcd: 390.0076, found: 390.0068; [M + Na]+: calcd: 411.9896, found: 411.9885; [2M + Na]+: calcd: 800.9894, found: 800.9878.

4-(4-Fluorophenyl)-2-(2-(4-phenylbutan-2-ylidene)hydrazinyl)thiazole (3c)

Beige solid; yield: 78%; M.p.: 181–183 °C; Rf: 0.53 (acetone/n-hexane, 1:3); λmax = 278, 365 nm; FTIR (ATR) cm–1: 3056 (=C–CH3 stretching), 2951 (C–H aliphatic stretching), 1618 (C=N stretching), 1598 (thiazole skeletal vibrations), 1558, 1489 (C=C aromatic ring stretchings), 1448 (C–H aliphatic bending), 1037–700 (characteristic thiazole vibrations); 1H NMR (400 MHz): δ (ppm) 7.75 (dd, 2H, Ar–H, J = 8.9, 5.1 Hz), 7.35–7.29 (m, 2H, Ar–H), 7.27–7.21 (m, 3H, Ar–H), 7.14 (t, 2H, Ar–H, J = 8.7 Hz), 6.73 (s, 1H, thiazole-H), 2.96 (t, 2H, −CH2–CH2–, J = 7.0 Hz), 2.70 (t, 2H, −CH2–CH2–, J = 7.0 Hz), 2.04 (s, 3H, −CH3); 19F NMR (375 MHz): δ (ppm) −114.63; 13C NMR (100 MHz): δ (ppm) 169.7 (thiazole ring C2), 163.1 (d, 1JCF = 249.4 Hz, Aripso), 155.7 (thiazole ring C4), 145.3(CH3–C=N−), 140.9, 128.5 (d, 3JCF = 11.4 Hz, Ar–C), 127.7 (d, 3JCF = 8.1 Hz, Ar–C), 126.2, 116.1 (d, 2JCF = 21.6 Hz, Ar–C), 101.8 (thiazole ring C5), 40.0 (−CH2–CH2–C=N−), 32.2 (−CH2–CH2−), 17.2 (CH3–CH2−); HRMS: m/z calcd for C19H18FN3S, [M + H]+: calcd: 340.1283, found: 340.1273; [M + Na]+: calculated: 362.1103, found: 362.1092; [2M + Na]+: calcd: 701.2308, found: 701.2290.

4-(4-Fluorophenyl)-2-(2-(4-(trifluoromethyl)benzylidene)hydrazinyl)thiazole (3d)

Off-white solid; yield: 74%; M.p.: 166–168 °C; Rf: 0.44 (acetone/n-hexane, 1:3); λmax = 268, 350 nm; FTIR (ATR) cm–1: 1693 (C=N stretching), 1570 (thiazole skeletal vibrations), 1489, 1438 (C=C aromatic ring stretchings), 1409 (C–H aliphatic bending), 1035–729 (characteristic thiazole vibrations); 1H NMR (400 MHz): δ (ppm) 8.26 (d, 1H, Ar–H, J = 8.3 Hz), 7.76 (ddt, 3H, Ar–H, J = 6.8, 5.4, 2.3 Hz), 7.69–7.63 (m, 3H, Ar–H), 7.16 (t, 2H, Ar–H, J = 8.7 Hz), 6.77 (s, 1H, thiazole-H); 19F NMR (375 MHz): δ (ppm) −62.72, −112.97; 13C NMR (100 MHz): δ (ppm) 170.6 (thiazole ring C2), 162.8 (d, 1JCF = 248.3 Hz, Aripso), 148.9 (thiazole ring C4), 141.5, 137.3 (H–C=N−), 130.4, 128.1 (d, 2JCF = 8.1 Hz, Ar–C), 126.8 (Ar–C), 125.6 (d, 4JCF = 3.9 Hz, Ar–C), 115.9 (d, 2JCF = 21.6 Hz, Ar–C), 103.2 (thiazole ring C5); HRMS: m/z calculated for C17H11F4N3S, [M + H]+: calcd: 366.0688, found: 366.0685; [M + Na]+: calcd: 388.0508, found: 388.0508; [2M + Na]+: calcd: 753.1118, found: 753.1098.

4-(4-Fluorophenyl)-2-(2-((5-methylfuran-2-yl)methylene)hydrazinyl)thiazole (3e)

Light-yellow solid; yield: 77%; M.p.: 142–143 °C; Rf: 0.50 (acetone/n-hexane, 1:3); λmax = 278, 353 nm; FTIR (ATR) cm–1: 2922 (C–H aliphatic stretching), 1610 (C=N stretching), 1490 (thiazole skeletal vibrations), 1450 (C=C aromatic ring stretchings), 1053–729 (characteristic thiazole vibrations); 1H NMR (400 MHz): δ (ppm) 7.89 (d, 1H, furan-H, J = 5.5 Hz), 7.85 (s, 1H, H–C=N−), 7.30–7.18 (m, 3H, Ar–H), 7.13–7.03 (m, 1H, Ar–H), 6.69 (d, 1H, furan-H, J = 3.3 Hz), 6.22 (s, 1H, thiazol-H), 2.35 (s, 3H, CH3−); 19F NMR (375 MHz): δ (ppm) −114.63; 13C NMR (100 MHz): δ (ppm) 168.5 (thiazole ring C2), 162.1 (d, 1JCF = 244.3 Hz, Aripso), 154.4 (thiazole ring C4), 149.8 (furan C2), 148.3 (H–C=N– azomethine), 132.3 (furan C5), 130.4, 127.9 (d, 3JCF = 8.4 Hz, Ar–C), 115.9 (d, 2JCF = 21.6 Hz, Ar–C), 114.4 (furan C4), 108.9 (furan C3), 103.7 (thiazole ring C5), 14.0 (CH3−); HRMS: m/z calcd for C15H12FN3OS, [M + H]+: 302.0763, found: 302.0749; [M + Na]+: calcd: 324.0583, found: 324.0569; [2M + Na]+: calcd: 625.1268, found: 625.1242.

2-(2-(1-(3-Bromophenyl)ethylidene)hydrazinyl)-4-(4-fluorophenyl)thiazole (3f)

Orange solid; yield: 72%; M.p.: 120–122 °C; Rf: 0.52 (acetone/n-hexane, 1:3); λmax = 267, 355 nm; FTIR (ATR) cm–1: 1670 (C=N stretching), 1598 (thiazole skeletal vibrations), 1571, 1508, 1442 (C=C aromatic ring stretchings), 1029–696 (characteristic thiazole vibrations); 1H NMR (400 MHz): δ (ppm) 11.39 (s, 1H, H–N−), 7.94 (s, 1H, Ar–H), 7.93–7.88 (m, 2H, Ar–H), 7.77 (d, 1H, Ar–H, J = 8.2 Hz), 7.57 (d, 1H, Ar–H, J = 8.9 Hz), 7.39 (t, 1H, Ar–H, J = 7.9 Hz), 7.32 (s, 1H, thiazole-H), 7.24 (t, 2H, Ar–H–C-F, J = 9.0 Hz), 2.32 (s, 3H, H3C–C=N−); 19F NMR (375 MHz): δ (ppm) −114.60; 13C NMR (100 MHz): δ (ppm) 170.2 (thiazole ring C2), 162.1 (d, 1JCF = 244.3 Hz, Aripso), 160.9 (thiazole ring C4), 145.3 (CH3–C=N−), 140.8, 131.7, 131.1, 128.6,127.9 (d, 3JCF = 8.1 Hz, Ar–C), 125.2 (Ar–C), 122.4 (Ar–C–Br), 115.9 (d, 2JCF = 21.6 Hz, Ar–C), 104.5 (thiazole ring C5), 14.4 (CH3–C=N−); HRMS: m/z calculated for C17H13BrFN3S, [M + H]+: calculated: 390.0076, found: 390.0071; [M + Na]+: calculated: 411.9896, found: 411.9889; [2M + Na]+: calculated: 800.9894, found: 800.9874.

4-(4-Fluorophenyl)-2-(2-(1-(4-fluorophenyl)ethylidene)hydrazinyl)thiazole (3g)

Lemon-yellow solid; yield: 70%; M.p.: 133–134 °C; Rf: 0.58 (acetone/n-hexane, 1:3); λmax = 266, 350 nm; FTIR (ATR) cm–1: 3057 (=C–H stretching), 2926 (C–H aliphatic stretching), 1605 (C=N stretching), 1485 (thiazole skeletal vibrations), 1442 (C=C aromatic ring stretchings), 1068–692 (characteristic thiazole vibrations); 1H NMR (400 MHz): δ (ppm) 11.26 (s, 1H, H–N−), 7.92 (dd, 2H, Ar–H, J = 8.9, 5.5 Hz), 7.83 (dd, 2H, Ar–H, J = 9.0, 5.5 Hz), 7.31 (s, 1H, thiazole-H), 7.25 (td, 4H, Ar–H, J = 8.8, 6.3 Hz), 2.33 (s, 3H, −CH3); 19F NMR (375 MHz): δ (ppm) −113.23, −114.67; 13C NMR (100 MHz): δ (ppm) 170.4 (thiazole ring C2), 163.7 (d, 1JCF = 244.3 Hz, Aripso), 161.3 (d, 1JCF = 244.3 Hz, Aripso), 150.1 (thiazole ring C4), 146.1 (H–C=N−), 134.9 (d, 4JCF = 3.3 Hz, Ar–C), 131.9 (Ar–C), 128.3 (d, 3JCF = 8.3 Hz, Ar–C), 127.9 (d, 3JCF = 8.3 Hz, Ar–C), 115.9 (d, 3JCF = 13.9 Hz, Ar–C–C–F), 115.7 (d, 3JCF = 13.9 Hz, Ar–C), 104.3 (thiazole ring C5), 14.5 (CH3 −C=N−); HRMS: m/z calculated for C17H13F2N3S, [M + H]+: calcd: 330.0876, found: 330.0865; [M + Na]+: calcd: 352.0696, found: 352.0682; [2M + Na]+: calcd: 681.1494, found: 681.1464.

4-Chloro-2-((2-(4-(4-fluorophenyl)thiazol-2-yl)hydrazinylidene)methyl)phenol (3h)

Orange solid; yield: 66%; M.p.: 192–193 °C; Rf: 0.27 (acetone/n-hexane, 1:3); λmax = 265, 358 nm; FTIR (ATR) cm–1: 3138 (O–H stretching), 3101 (=C–H stretching), 2924 (C–H aliphatic stretching), 1610 (C=N stretching), 1562 (thiazole skeletal vibrations), 1477 (C=C aromatic ring stretchings), 1031–734 (characteristic thiazole vibrations); 1H NMR (400 MHz): δ (ppm) 12.25 (s, 1H, H–N−), 10.36 (s, 1H, H–O), 8.28 (s, 1H, H–C=N−), 7.89 (dd, 2H, Ar–H, J = 8.8, 5.6 Hz), 7.63 (d, 2H, Ar–H, J = 2.8 Hz), 7.30 (s, 1H, thiazole-H), 7.28–7.17 (m, 3H, Ar–H), 6.93 (d, 1H, Ar–H, J = 8.8 Hz); 19F NMR (375 MHz): δ (ppm) −114.49; 13C NMR (100 MHz): δ (ppm) 168.5 (thiazole ring C2), 162.1 (d, 1JCF = 244.7 Hz, Aripso), 155.1 (thiazole ring C4), 149.1(Ar–C–OH), 137.8 (H–C=N−), 131.7, 130.3 (Ar–C), 127.9 (d, 3JCF = 8.1 Hz, Ar–C), 125.2 (Ar–C), 123.7 (Ar–C-Cl), 122.6, 118.4 (Ar–C), 115.9 (d, 3JCF = 21.3 Hz, Ar–C), 103.8 (thiazole ring C5); HRMS: m/z calcd for C16H11ClFN3OS, [M + H]+: calcd: 348.0373, found: 348.0365; [M + Na]+: calcd: 370.0193, found: 370.0190; [2M + Na]+: calcd: 717.0488, found: 717.0472.

4-(4-Fluorophenyl)-2-(2-(3-(trifluoromethyl)benzylidene)hydrazinyl)thiazole (3i)

Gray solid; yield: 72%; M.p.: 157–159 °C; Rf: 0.38 (acetone/n-hexane, 1:3); λmax = 264, 358 nm; FTIR (ATR) cm–1: 3061 (=C–H stretching), 2929 (C–H aliphatic stretching), 1695 (C=N stretching), 1570 (thiazole skeletal vibrations), 1500, 1448 (C=C aromatic ring stretchings), 1068–736 (characteristic thiazole vibrations); 1H NMR (400 MHz): δ (ppm) 8.13 (s, 1H, H–C=N−), 7.97 (d, 2H, Ar–H, J = 8.7 Hz), 7.90 (dd, Ar–H, J = 8.9, 5.5 Hz), 7.73–7.65 (m, 2H, Ar–H), 7.34 (s, 1H, thiazole-H), 7.24 (t, 2H, Ar–H, J = 8.8 Hz); 19F NMR (375 MHz): δ (ppm) −61.39, −114.54; 13C NMR (100 MHz): δ (ppm) 168.6 (thiazole ring C2), 162.1 (d, 1JCF = 244.7 Hz, Aripso), 150.0 (thiazole ring C4), 139.9 (H–C=N−), 136.1, 131.7 (d, 4JCF = 3.3 Hz, Ar–C), 130.4 (d, 3JCF = 11.7 Hz, Ar–C), 129.9, 127.9 (d, 3JCF= 8.1 Hz, Ar–C), 125.9, 123.2, 122.9 (d, 4JCF = 4.0 Hz, Ar–C), 115.9 (d, 2JCF = 21.3 Hz, Ar–C), 104.3 (thiazole ring C5); HRMS: m/z calcd for C17H11F4N3S, [M + H]+: calcd: 366.0688, found: 366.0680; [2M + Na]+: calcd: 753.1118, found: 753.1086.

2-(2-(2-Ethoxybenzylidene)hydrazinyl)-4-(4-fluorophenyl)thiazole (3j)

Light-yellow solid; yield: 78%; M.p.: 127–128 °C; Rf: 0.40 (acetone/n-hexane, 1:3); λmax = 265, 370 nm; FTIR (ATR) cm–1: 2930 (C–H aliphatic stretching), 1607 (C=N stretching), 1500 (thiazole skeletal vibrations), 1495, 1457 (C=C aromatic ring stretchings), 1018–703 (characteristic thiazole vibrations); 1H NMR (400 MHz): δ (ppm) 8.41 (s, 1H, H–C=N−), 7.89 (dd, Ar–H, J = 8.9, 5.5 Hz), 7.79 (d, 1H, Ar–H, J = 7.8 Hz), 7.37–7.20 (m, 4H, Ar–H), 7.08–6.95 (m, 3H, Ar–H), 4.14–4.07 (m, 2H, −CH2–CH3), 1.38 (t, 3H, CH3–CH2–, J = 7.0 Hz); 19F NMR (375 MHz): δ (ppm) −114.63; 13C NMR (100 MHz): δ (ppm) 168.8 (thiazole ring C2), 164.7 (d, 1JCF = 285.4 Hz, Aripso), 160.9 (Ar–C–O) 156.9, 149.9 (thiazole ring C4), 137.7 (H–C=N−), 131.8 (d, 4JCF = 2.9 Hz, Ar–C), 131.1 (Ar–C), 127.9 (d, J = 8.1 Hz, Ar–C), 125.4, 123.1, 121.2 (Ar–C), 115.9 (d, 2JCF = 21.3 Hz), 113.3 (Ar–C), 103.8 (thiazole ring C5), 64.3 (CH3–CH2–O−), 15.1 (CH3–CH2−); HRMS: m/z calculated for C18H16FN3OS, [M + H]+: calcd: 342.1076, found: 342.1058; [M + Na]+: calcd: 364.0896, found: 364.0882; [2M + Na]+: calcd: 705.1894, found: 705.1853.

4-(4-Fluorophenyl)-2-(2-(2-(trifluoromethyl)benzylidene)hydrazinyl)thiazole (3k)

Off-white solid; yield: 79%; M.p.: 168–169 °C; Rf: 0.49 (acetone/n-hexane, 1:3); λmax = 265, 364 nm; FTIR (ATR) cm–1: 3057 (=C–H stretching), 2933 (C–H aliphatic stretching), 1699 (C=N stretching), 1572 (thiazole skeletal vibrations), 1499, 1446 (C=C aromatic ring stretchings), 1060–734 (characteristic thiazole vibrations); 1H NMR (400 MHz): δ (ppm) 12.50 (s, 1H, H–N−), 8.37 (s, 1H, H–C=N−), 8.14 (d, 1H, Ar–H, J = 7.8 Hz), 7.90 (dd, 2H, Ar–H, J = 8.8, 5.6 Hz), 7.81–7.72 (m, 2H, Ar–H), 7.58 (t, 1H, Ar–H, J = 7.6 Hz), 7.37 (s, 1H, thiazole-H), 7.25 (t, 2H, Ar–H, J = 8.9 Hz); 19F NMR (375 MHz): δ (ppm) −57.06, −114.48; 13C NMR (100 MHz): δ (ppm) 168.3 (thiazole ring C2), 162.1 (d, 1JCF = 244.7 Hz, Aripso), 150.1 (thiazole ring C4), 136.6 (H–C=N−), 133.3, 132.7, 131.6, 129.7, 128.1 (d, 3JCF = 8.1 Hz, Ar–C), 127.9, 126.6–126.1 (m, Ar–C), 115.9 (d, 2JCF = 21.6 Hz, Ar–C), 104.5 (thiazole ring C5); HRMS: m/z calculated for C17H11F4N3S, [M + H]+: calcd: 366.0688, found: 366.0680; [2M + Na]+: calcd: 753.1118, found: 753.1086.

2-(2-(3-Fluoro-2-methoxybenzylidene)hydrazinyl)-4-(4-fluorophenyl)thiazole (3l)

Light-yellow solid; yield: 61%; M.p.: 115–117 °C; Rf: 0.39 (acetone/n-hexane, 1:3); λmax = 276, 368 nm; FTIR (ATR) cm–1: 3055 (=C–H stretching), 1604 (C=N stretching), 1575 (thiazole skeletal vibrations), 1489, 1444 (C=C aromatic ring stretching), 1006–696 (characteristic thiazole vibrations); 1H NMR (400 MHz): δ (ppm) 8.29 (s, 1H, H–C=N−), 7.90 (dd, 2H, Ar–H, J = 8.9, 5.5 Hz), 7.63 (d, 1H, Ar–H, J = 8.0 Hz), 7.33 (s, 1H, thiazole-H), 7.31–7.21 (m, 3H, Ar–H), 7.18 (td, 1H, Ar–H, J = 8.2, 5.1 Hz), 3.91 (s, 3H, −CH3); 19F NMR (375 MHz): δ (ppm) −114.55, −131.04; 13C NMR (100 MHz): δ (ppm) 168.6 (thiazole ring C2), 162.1 (d, 1JCF = 244.3 Hz, Aripso), 155.7 (d, 1JCF = 245.0 Hz, Aripso), 150.0 (thiazole C4), 145.8 (Ar–C–O), 136.1 (H–C=N−), 131.7 (d, 4JCF = 2.9 Hz, Ar–C), 129.5 (d, 4JCF = 2.9 Hz, Ar–C), 127.9 (d, 3JCF = 8.4 Hz, Ar–C), 124.9 (d, 3JCF = 8.1 Hz, Ar–C), 121.1 (d, 4JCF = 3.3 Hz, Ar–C), 117.8 (d, 2JCF = 19.1 Hz, Ar–C), 115.9 (d, 2JCF = 21.6 Hz, Ar–C), 104.2 (thiazole ring C5), 62.5 (d, 5JHF = 5.1 Hz, −OCH3); HRMS: m/z calculated for C17H13F2N3OS, [M + H]+: calcd: 346.0825, found: 346.0823; [M + Na]+: calcd: 368.0645, found: 368.0642; [2M + Na]+: calcd: 713.1392, found: 713.1378.

2-(2-((1H-Pyrrol-2-yl)methylene)hydrazinyl)-4-(4-fluorophenyl)thiazole (3m)

Dark-gray solid; yield: 77%; M.p.: 130–132 °C; Rf: 0.45 (acetone/n-hexane, 1:3); λmax = 282, 358 nm; FTIR (ATR) cm–1: 3278 (N–H stretching), 1626 (C=N stretching), 1593 (thiazole skeletal vibrations), 1500 (C=C aromatic ring stretchings), 1029–730 (characteristic thiazole vibrations); 1H NMR (400 MHz): δ (ppm) 11.77 (s, 1H, H–N−), 11.21 (s, 1H, H–N, pyrrole), 7.91 (s, 1H, H–C=N−), 7.88 (dd, 2H, Ar–H, J = 8.9, 5.6 Hz), 7.30–7.18 (m, 3H, Ar–H), 6.90 (d, 1H, pyrrole-H, J = 1.5 Hz), 6.40 (s, 1H, thiazole), 6.12 (d, 1H, pyrrole-H, J = 3.6 Hz); 19F NMR (375 MHz): δ (ppm) −114.77; 13C NMR (100 MHz): δ (ppm) 168.8 (thiazole ring C2), 162.0 (d, 1JCF = 244.3 Hz, Aripso), 154.7 (thiazole ring C4), 149.7, 135.5 (H–C=N−), 131.9 (pyrrole C2), 127.9 (d, 3JCF = 8.1 Hz, Ar–C), 127.6 (Ar–C), 122.1 (pyrrole C3), 115.9 d, 2JCF = 21.6 Hz, 111.8 (Ar–C), 109.6 (pyrrole-C5), 103.3 (thiazole ring C5).

4-(4-Fluorophenyl)-2-(2-(thiophen-2-ylmethylene)hydrazinyl)thiazole (3n)

Yellow solid; yield: 67%; M.p.: 143–145 °C; Rf: 0.54 (acetone/n-hexane, 1:3); λmax = 279, 358 nm; FTIR (ATR) cm–1: 1602 (C=N stretching), 1479 (C=C aromatic ring stretching), 1004–777 (characteristic thiazole vibrations); 1H NMR (400 MHz): δ (ppm) 8.23 (s, 1H, H–C=N−), 7.89 (dd, 2H, Ar–C, J = 8.9, 5.6 Hz), 7.58 (d, 1H, thiophene C5–H, J = 5.0 Hz), 7.37 (d, 1H, thiophene C3–H, J = 2.5 Hz), 7.29 (s, 1H, thiazole-H), 7.24 (t, 2H, Ar–H, J = 8.9 Hz), 7.10 (dd, 1H, Ar–H, J = 5.1, 3.5 Hz); 19F NMR (375 MHz): δ (ppm) −114.57; 13C NMR (100 MHz): δ (ppm) 168.4 (thiazole ring C2), 162.1 (d, 1JCF = 244.3 Hz, Aripso), 149.9 (thiophene C2), 139.6 (thiophene C3), 137.2 (H–C=N−), 131.7, 129.6, 128.2 (d, 2JCF = 18.0 Hz, Ar–C), 127.9 (d, 3JCF = 8.1 Hz, Ar–C), 115.9 (d, 2JCF = 21.3 Hz, Ar–C), 103.9 (thiazole ring C5); HRMS: m/z calcd for C14H10FN3S2, [M + H]+: calcd: 304.0378, found: 304.0375; [M + Na]+: calcd: 326.0198, found: 326.0193; [2M + Na]+: calcd: 629.0498, found: 629.0487.

4-(4-Fluorophenyl)-2-(2-(2-(methylthio)benzylidene)hydrazinyl)thiazole (3o)

Pink solid; yield: 80%; M.p.: 152–154 °C; Rf: 0.48 (acetone/n-hexane, 1:3); λmax = 287, 357 nm; FTIR (ATR) cm–1 = 3138 (N–H stretching), 3053 (=C–H stretching), 1601 (C=N stretching), 1489, 1446 (C=C aromatic ring stretchings), 1411 (C–H aliphatic bending), 1006–731 (characteristic thiazole vibrations); 1H NMR (400 MHz): δ (ppm) 8.43 (s, 1H, H–C=N−), 7.90 (dd, 2H, Ar–C, J = 8.9, 5.5 Hz), 7.74 (d, 1H, Ar–H, J = 8.5 Hz), 7.40–7.33 (m, 2H, Ar–H), 7.31 (s, 1H, thiazole-H), 7.24 (td, 3H, Ar–H, J = 8.5, 3.7 Hz), 2.50 (s, 3H, CH3–S); 19F NMR (375 MHz): δ (ppm) −114.53; 13C NMR (100 MHz): δ (ppm) 168.7 (thiazole ring C2), 162.1 (d, 1JCF = 244.3 Hz, Aripso), 149.9 (thiazole C4), 139.6 (H–C=N−), 137.8 (Ar–C–S), 132.2, 131.7 (d, 4JCF = 3.3 Hz, Ar–C), 130.0, 127.9 (d, 3JCF = 8.1 Hz, Ar–C), 127.0 (d, 2JCF = 30.1 Hz, Ar–C), 125.7, 115.9 (d, 2JCF = 21.6 Hz, Ar–C), 104.1 (thiazole ring C5), 16.2 (CH3–S); HRMS: m/z calculated for C17H14FN3S2; [M + H]+: calcd: 344.0691, found: 344.0688; [M + Na]+: calcd: 366.0511, found: 366.0507; [2M + Na]+: calcd: 709.1124, found: 709.1124.

(Please see the Supporting Information for protocols of α-amylase, antiglycation inhibition, antioxidant, in vitro hemolysis, and molecular docking studies).

Acknowledgments

The authors extend their appreciation to the Researcher Supporting Project number (RSP2023R431), King Saud University, Riyadh, Saudi Arabia, for funding this research work. Dr. Muhammad Khalid gratefully acknowledges the financial support of HEC Pakistan (project no. 20-14703/NRPU/R&D/HEC/2021). H.M. is thankful to HEC Pakistan for the award of IRSIP fellowship for the University of Nottingham. The authors are also thankful for the cooperation and collaboration of A.A.C.B from IQ-USP, Brazil, especially for his continuous support and providing computational lab facilities.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.3c00265.

  • UV–vis, FTIR, 1H, 13C, 19-F NMR, and HRMS spectra of all compounds, and protocols of all biological assays along with molecular docking experiment (PDF)

Author Contributions

Dr. Muhammad Khalid, confirm that all authors played their role in this work and is briefed as follows: H.M.: performed all experimental work, characterization, and write-up; M.H.: data compilation, assisting in syntheses, and write-up; T.A.: supervisor of the first author, designed the project, refined the paper, and also corresponding author; S.W.: assisted first author (characterization) in his lab, paper writing, and improvement; M.K., M.A.A., R.B., R.O., S.P.: molecular docking and writing of the part.

The authors declare no competing financial interest.

Supplementary Material

ao3c00265_si_001.pdf (7.4MB, pdf)

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