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Article

Synthesis and Biological Activity Evaluation of Novel 5-Methyl-7-phenyl-3H-thiazolo[4,5-b]pyridin-2-ones

by
Andrii Lozynskyi
1,
Yulian Konechnyi
2,
Julia Senkiv
3,
Ihor Yushyn
1,
Dmytro Khyluk
4,
Olexandr Karpenko
5,
Yulia Shepeta
6 and
Roman Lesyk
1,7,*
1
Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, 69 Pekarska, 79010 Lviv, Ukraine
2
Department of Microbiology, Danylo Halytsky Lviv National Medical University, 69 Pekarska, 79010 Lviv, Ukraine
3
Institute of Cell Biology, NAS of Ukraine, 14/16 Drahomanova, 79005 Lviv, Ukraine
4
Department of Organic Chemistry, Medical University of Lublin, Aleje Racławickie 1, 20-059 Lublin, Poland
5
Enamine Ltd., 23 Alexandra Matrosova, 01103 Kyiv, Ukraine
6
Department of Pharmaceutical Chemistry, National Pirogov Memorial Medical University, 56 Pirogov, 21018 Vinnytsya, Ukraine
7
Department of Biotechnology and Cell Biology, Medical College, University of Information Technology and Management in Rzeszow, Sucharskiego 2, 35-225 Rzeszow, Poland
*
Author to whom correspondence should be addressed.
Sci. Pharm. 2021, 89(4), 52; https://doi.org/10.3390/scipharm89040052
Submission received: 26 October 2021 / Revised: 20 November 2021 / Accepted: 23 November 2021 / Published: 25 November 2021
(This article belongs to the Special Issue Heterocyclic Chemistry in Drug Design 2.0)
Browse Figures
Versions Notes

Abstract

:
A series of 5-methyl-7-phenyl-3H-thiazolo[4,5-b]pyridin-2-ones has been designed, synthesized, and characterized by spectral data. Target compounds were screened for their antimicrobial activity against some pathogenic bacteria and fungi, and most of them showed moderate activity, especially compound 3g, which displayed the potent inhibitory effect against Pseudomonas aeruginosa and Escherichia coli with MIC value of 0.21 μM. The active thiazolopyridine derivatives 3c, 3f, and 3g were screened for their cytotoxicity effects on HaCat, Balb/c 3T3 cells using MTT assay, which revealed promising results. In silico assessment for compounds 3c, 3f, and 3g also revealed suitable drug-like parameters and ADME properties. The binding interactions of the most active compound 3g were performed through molecular docking against MurD and DNA gyrase, with binding energies and an inhibitory constant compared to the reference drug ciprofloxacin. The tested thiazolo[4,5-b]pyridines constitute an exciting background for the further development of new synthetic antimicrobial agents.

1. Introduction

Pyridine-based derivatives are a known class of heterocyclic compounds that underly the structure of many vitamins, alkaloids, disinfectants, herbicides, and medicines [1,2]. The pharmacological significance of these compounds is related to easy metabolism in the human body by N-methylation and N- and C-oxidation pathways [3]. On the other hand, the toxic effect of these compounds is also well established [4,5]. It is worth mentioning that the main interest in searching for pharmacologically attractive pyridines is devoted to their condensed analogs due to their diverse biological activity and clinical applications. Thus, condensed heterocyclic systems with a pyridine moiety in the structure occur in many commercially available drugs with different mechanisms of biological activity (Figure 1). In addition, fused pyridine-based heterocycles have been identified as potent antimicrobial [6,7], anticancer [8,9], antichagasic [10], antioxidant [11,12], and anti-inflammatory agents [13,14]. Furthermore, some fused pyridine derivatives were found to be inhibitors of glycogen synthase kinase-3 (GSK-3) [15], CDK5 protein kinase [16], tyrosyl-tRNA synthetase [17], cdc2-like kinase 1 (CLK1) [18], and tumor necrosis factor-α (TNF-α) [19].
The effective way to obtain potential drug-like molecules, including fused pyridine derivatives, is through the reactions of aminoazoles as binucleophiles with various electrophiles [20,21,22]. The reactions of aminoazoles with α,β-unsaturated aldehydes and ketones, α-ketoacids, ketoesters, β-dicarbonyls yielding fused pyridine derivatives have been reported previously [23,24,25] (Figure 2). The mentioned carbonyl compounds with an unsaturated chain are also effective reagents in other pericyclic reactions, especially the Diels–Alder reaction with dienophiles in constructing different polycyclic systems [26,27,28].
The current work is devoted to the synthesis and study of the biological activity of condensed pyridine derivatives, namely thiazolopyridines. Thus, a combination of thiazole ring with biologically relevant pyridine fragment is a practical direction in creating potential biologically active compounds within a hybrid-pharmacophore approach. This approach allows for the obtaining of new classes of organic compounds with enhanced activity and reduced toxicity [29]. Some thiazolopyridines have been studied successfully as antioxidant [30], anti-inflammatory [31], antifungal [32], and herbicidal agents [33]. In addition, in our previous studies, we reported the synthesis of thiazolo[4,5-b]pyridines via the [3 + 3]-cyclization of 4-amino-5H-thiazol-2-one and chalcones and arylidene pyruvic acids (APAs), which demonstrated anticancer [25,34] and antimicrobial activities [35].
Given our interest in searching and studying new low molecular weight compounds among fused pyridines, herein, we report the synthesis, structure elucidation, and in vitro antimicrobial, cytotoxic activity evaluation and docking studies of some novel 5-methyl-7-phenyl-3H-thiazolo[4,5-b]pyridin-2-ones. This manuscript is intended to draw attention to the chemistry and pharmacology of the thiazolopyridines and its further examination as potent drug candidates.

2. Materials and Methods

2.1. General Information

All materials were purchased from commercial sources and used without purification. Melting points were measured in open capillary tubes and were uncorrected. The elemental analyses were performed using the Thermo Scientific FlashSmart Elemental Analyzer. The 1H and 13C NMR spectra were recorded on Varian Gemini (1H at 400 and 13C at 100 MHz) instrument in DMSO-d6. Chemical shifts (δ) are given in ppm units relative to tetramethylsilane as reference (0.00). LC-MS was performed using a system with an Agilent 1100 Series HPLC equipped with diode-array detector and Agilent LC\MSD SL mass-selective detector using chemical ionization at atmospheric pressure (APCI). The reaction mixture was monitored by thin-layer chromatography (TLC) using Silufol-254 plates. Starting 4-amino-5H-thiazol-2-one and benzylideneacetones were prepared according to reported methods [36,37].

2.2. Synthesis and Characterization of Compounds

General Procedure for the Synthesis of 5-Methyl-7-Phenyl-3H-Thiazolo[4,5-b]Pyridin-2-Ones 3a–g

A mixture of benzylideneacetone (1.0 mmol) and 4-amino-5H-thiazol-2-one (1.0 mmol) was refluxed for 3 h in glacial acetic acid (10 mL) (monitored by TLC). After completion, the reaction mixture was cooled and left overnight at room temperature. The solid precipitates were filtered off, washed with methanol (5–10 mL), and recrystallized from a mixture of DMF: acetic acid (1:2) or glacial acetic acid. The resulting powders were filtered and washed with acetic acid, water, methanol, and diethyl ether, successively. The final products were dried at room temperature until constant weight.
7-(4-Methoxyphenyl)-5-methyl-3H-thiazolo[4,5-b]pyridin-2-one (3a). Yield 71%, mp > 240 °C (AcOH). 1H NMR (400 MHz, DMSO-d6): δ 2.47 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 7.10 (d, 2H, J = 8.6 Hz, arom.), 7.15 (s, 1H, CH), 7.59 (d, 2H, J = 8.6 Hz, arom.), 12.55 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): δ 23.8, 55.8, 113.4, 115.1, 117.1, 129.2, 131.8, 138.6, 143.2, 150.4, 153.4, 160.6. ESI-MS m/z 273 (M + H)+. Anal. Calcd for C14H12N2O2S: C, 61.75; H, 4.44; N, 10.29. Found: C, 61.62; H, 4.34; N, 10.38.
7-(4-Dimethylaminophenyl)-5-methyl-3H-thiazolo[4,5-b]pyridin-2-one (3b). Yield 74%, mp > 240 °C (DMF:EtOH). 1H NMR (400 MHz, DMSO-d6): δ 2.45 (s, 3H, CH3), 2.97 (s, 6H, N(CH3)2), 6.83 (d, 2H, J = 8.8 Hz, arom.), 7.12 (s, 1H, CH), 7.50 (d, 2H, J = 8.8 Hz, arom.), 12.48 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): δ 23.7, 37.4, 112.6, 116.2, 123.5, 128.6, 136.6, 143.6, 146.0, 151.4, 156.8, 162.0. ESI-MS m/z 286 (M + H)+. Anal. Calcd for C15H15N3OS: C, 63.13; H, 5.30; N, 14.72. Found: C, 63.22; H, 5.40; N, 14.68.
7-(4-Fluorophenyl)-5-methyl-3H-thiazolo[4,5-b]pyridin-2-one (3c). Yield 67%, mp 220–222 °C (AcOH). 1H NMR (400 MHz, DMSO-d6): δ 2.48 (s, 3H, CH3), 7.18 (s, 1H, CH), 7.38 (t, 2H, J = 8.8 Hz, arom.), 7.68 (dd, 2H, J = 5.3, 8.8 Hz, arom.), 12.55 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): δ 20.0, 110.7, 116.8, 124.3, 130.2, 142.4 (d, J  =  6.0 Hz, C–F), 144.8, 157.5 (d, J  =  30.0 Hz, C–F), 162.9, 165.2, 166.5 (d, J  =  220.0 Hz, C–F), 169.1. ESI-MS m/z 261 (M + H)+. Anal. Calcd for C13H9FN2OS: C, 59.99; H, 3.49; N, 10.76. Found: C, 60.09; H, 3.32; N, 10.68.
7-(3-Hydroxy-4-methoxyphenyl)-5-methyl-3H-thiazolo[4,5-b]pyridin-2-one (3d). Yield 65%, mp > 240 °C (AcOH). 1H NMR (400 MHz, DMSO-d6): δ 2.38 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 7.03–7.05 (m, 3H, arom.), 7.09 (s, 1H, CH), 9.36 (s, 1H, OH), 12.49 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): δ 21.1, 56.1, 113.0, 119.0, 122.5, 129.5, 130.8, 138.4, 143.4, 147.4, 149.2, 153.6, 165.6, 169.3. ESI-MS m/z 289 (M + H)+. Anal. Calcd for C14H12N2O3S: C, 58.32; H, 4.20; N, 9.72. Found: C, 58.45; H, 4.32; N, 9.61.
7-(4-Chlorophenyl)-5-methyl-3H-thiazolo[4,5-b]pyridin-2-one (3e). Yield 73%, mp > 240 °C (DMF:EtOH). 1H NMR (400 MHz, DMSO-d6): δ 2.49 (s, 3H, CH3), 7.20 (s, 1H, CH), 7.61–7.68 (m, 4H, arom.), 12.64 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): δ 23.8, 117.4, 120.1, 129.6, 129.7, 134.7, 135.8, 142.1, 156.6, 160.1, 163.4. ESI-MS m/z 277/279 (M + H)+. Anal. Calcd for C13H9ClN2OS: C, 56.42; H, 3.28; N, 10.12. Found: C, 56.30; H, 3.34; N, 10.19.
7-(4-Bromophenyl)-5-methyl-3H-thiazolo[4,5-b]pyridin-2-one (3f). Yield 74%, mp > 240 °C (DMF:EtOH). 1H NMR (400 MHz, DMSO-d6): δ 2.49 (s, 3H, CH3), 7.21 (s, 1H, CH), 7.59 (d, 2H, J = 8.4 Hz, arom.), 7.76 (d, 2H, J = 8.4 Hz, arom.), 12.64 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): δ 23.8, 115.4, 117.3, 123.4, 129.9, 132.7, 136.2, 142.2, 150.9, 165.2, 169.0. ESI-MS m/z 321/323 (M + H)+. Anal. Calcd for C13H9BrN2OS: C, 48.61; H, 2.82; N, 8.72. Found: C, 48.52; H, 2.91; N, 8.59.
7-(3,4-Dimethoxyphenyl)-5-methyl-3H-thiazolo[4,5-b]pyridin-2-one (3g). Yield 68%, mp 236–238 °C (AcOH). 1H NMR (400 MHz, DMSO-d6): δ 2.40 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 7.13 (s, 1H, CH), 7.19–7.21 (m, 3H, arom.), 12.54 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): δ 27.6, 54.5, 56.0, 110.8, 112.0, 123.4, 125.6, 127.5, 143.9, 149.4, 151.4, 155.0, 158.6, 162.7, 164.9. ESI-MS m/z 303 (M + H)+. Anal. Calcd for C15H14N2O3S: C, 55.59; H, 4.67; N, 9.27. Found: C, 55.40; H, 4.54; N, 9.19.

2.3. Antimicrobial Activity

The synthesized compounds were tested in vitro for their antibacterial and antifungal activities using the agar diffusion and serial dilutions resazurin-based microdilution assays (RBMA) [38,39]. For this purpose, 100 μL (1 mg/mL) of the tested compound was placed in an agar well with a diameter of 5.5 mm. The diameter of the growth retardation was measured using a micrometer with an error of 0.1 mm. Dimethyl sulfoxide (DMSO), vancomycin (discs), ciprofloxacin (discs), and clotrimazole (discs) were used as a control. Pure DMSO was used as a solvent due to the poor solubility of the test compounds in dilute DMSO. In addition, Mueller–Hinton agar and Saburo agar (for fungi) were used, and Petri dishes were incubated at 37 °C for 24 h for bacteria and at 25 °C for 24–48 h for fungi. The RBMA method involved the introduction of a 96-well plate 50 μL of nutrient medium (Mueller–Hinton broth or glucose broth), 50 mL of a suspension of the microorganism (McFarland 2.0), and 100 μL of tested compounds, with the addition of 15 μL of 0.02% resazurin in each well. Sixteen reference and clinical microbial and fungal strains were used (Table 1), previously identified by the MALDI TOF system (Bruker, Bremen, Germany), and 16S rRNA gene sequences. All clinical strains were multidrug-resistant or extensively drug-resistant with different antibiotic resistance patterns. Clinical strains were isolated from a patient with healthcare-associated infections from regional hospitals. All testing was repeated in triplicate.

2.4. MTT Assay

The cytotoxic effect of new thiazolopyridine derivatives on pseudonormal cell lines was evaluated using MTT assay. The 4 × 104 cells/mL human epidermal keratinocytes (HaCat cell line) or normal murine fibroblasts (BALB/c 3T3 cell line) were seeded in 96-well plates in 100 µL DMEM medium, supplemented with 10% FBS and incubated for 24 h to attach at 37C in CO2 incubator. The HaCaT human skin keratinocyte cell line and normal murine fibroblasts (BALB/c 3T3) were kindly gifted by the R.E. Kavetsky Institute of experimental pathology, oncology and radiobiology NAS of Ukraine (Kyiv, Ukraine). The next day, they were treated with studied compounds at concentrations 10, 25, 50, 150, and 250 µM. After 72 h compound exposure, 20 μL MTT reagent was added, incubated for 4 h, and measured according to the manufacturer’s recommendations (Merck KGaA, Burlington, MA, USA).

2.5. Molecular Docking

Molecular docking is the most widespread method for the calculation and prediction of protein–ligand interactions. Before docking procedures, we analyzed available literature data for choosing the most logical and appropriate biological targets. There are literally reported 4-thiazolidinones derivatives, which demonstrate antibacterial activities through MurD ligase inhibition [40]. Moreover, the well-known DNA gyrase inhibitors fluoroquinolones are based on the core, which are quite similar to 3H-thiazolo[4,5-b]pyridin-2-one. Additionally, structurally related 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole-based derivatives were identified as DNA gyrase inhibitors [41]. That is why MurD ligase (PBD code 2Y67) [42] and DNA gyrase (PBD code 2XCT) [43] were chosen for docking in silico simulations with the aim of receiving the necessary data for a suggestion about the possible mechanism of antibacterial activity for our lead compound 3g.
The X-ray crystal structures of target proteins were downloaded from the Protein Data Bank (RCSB PDB: Homepage. Available online: https://www.rcsb.org/ (accessed on 20 August 2021)). The AutoDock Tools were used for preparing the enzymes for docking, which includes removing all bound ligands and water molecules, adding polar hydrogen atoms, and defining all rotatable bonds [44]. Moreover, Kollman charges were computed and spread over all atoms in residues. The chemical structure of 3g was made using Biovia Draw and energy minimization was carried out by Hyperchem 7.5 using an AM1 quantum technique until the RMS gradient was less than 0.01 kcal /(mol Å). The three-dimensional grid boxes were created with the size 50 × 50 × 50 xyz points, the spacing between grid points was 0.375 Å, and the grid maps representing the intact ligand in the actual docking target site were made by Auto Grid Tool. For more accurate results, we changed Lamarckian Genetic Algorithm (LGA) parameters from the default setting to enhanced, including 100 runs, 300 populations, and 2,50,0000 energy evaluations, a mutation rate of 0.02, and a crossover rate of 0.80 [45]. The interactions were estimated in terms of binding energy (kcal/mol) and inhibition constant (µM) along with the number of hydrogen bonds formed with the surrounding amino acid residues. The validations of selected docking parameters were performed by redocking of the initial ligands from the used enzyme structures. The accuracies of the redocking experiments were assessed by calculating the root-mean-square deviations (RMSD) and cutting off the results with RMSD > 2. Visualization and interpretation of obtained data were performed by Discovery Studio Visualizer of Dassault Systemes Biovia ® (Vélizy-Villacoublay, Yvelines, France).

3. Results and Discussion

3.1. Synthesis

In this article, we performed the condensation reaction of 4-amino-5H-thiazol-2-one with benzylideneacetone, leading to 5-methyl-7-phenyl-3H-thiazolo[4,5-b]pyridin-2-ones using conventional thermal heating conditions (Scheme 1). The starting benzylideneacetones 2a–g were synthesized according to the known literature procedures by reaction of aromatic aldehydes and acetone in an aqueous solution of potassium hydroxide and were subsequently used directly without additional purification. Analytical and spectral data (1H and 13C NMR) confirmed the structure of the synthesized compounds (copies of the corresponding spectra are presented in the Supplementary Material). The 1H NMR spectra of the fused pyridine analogs 3a–g exhibit singlets for the CH group of the pyridine ring at ~ 7 ppm and broad peaks due to the NH–functionalities around 12 ppm. In the 13C NMR spectra of the synthesized compounds, the signals observed at δ 160.6–162.0 are assigned to the carbonyl group (C=O). Carbon signals of the methyl group were observed at δ 23.7–23.8 ppm.

3.2. Biological Activity

Antimicrobial resistance (AMR) is a global healthcare problem, and there is a close interrelationship between the progressing of AMR in the world and the increase in mortality from infectious diseases, mainly through healthcare-associated infections (HAIs) [46]. According to a WHO prognosis, mortality from AMR pathogens in the world by 2050 will take first place in the overall structure of causes of death and will exceed the mortality of cancer. According to the WHO recommendation, discovering new synthetic molecules with antimicrobial action is one of the leading short-term approaches to control AMR pathogens. 4-Thiazolidinone-based derivatives are one of the promising classes of compounds with a polypharmacological profile, which contain several reaction centres in the basic heterocycle and are relatively easily adapted for chemical modification. That is why this class of chemical compounds is useful in the search for a “drug-like molecule” with antimicrobial action, effective against the variable mechanisms of AMR, including HAIs pathogens.
Thus, according to the screening of the antimicrobial activity of 5-methyl-7-phenyl-3H-thiazolo[4,5-b]pyridin-2-ones, the best activity was shown by the compound 3g, which showed antifungal activity against fungi of the genus Candida, selective action against Gram-positive microorganism Micrococcus luteus, and selective action on few Gram-negative microorganisms (Table 1 and Figure 3). In Figure 3, it is shown that compounds 3a (light blue colour), 3c (grey colour), 3f (green colour), and 3g (dark clue colour) have a bigger growth inhibition zone than solvent control (brown colour).
Compounds 3f and 3d exhibited the highest antifungal activity, both for fungi of the genus Candida and fungus of the genus Saccharomyces. These compounds have also been active against some Gram-negative microorganisms, particularly against clinical strains of Citrobacter freundii and Achromobacter xylosoxidans.
Four compounds (3a, 3c, 3f, 3g) showed significant antimicrobial activity against both clinical and reference Gram-negative microorganisms.
The tested compounds did not show significant antimicrobial activity against Gram-positive microorganisms, except for the compound 3g, active against Micrococcus luteus. Four lead-compounds (Table 2) were tested for the minimum inhibitory concentration (MIC). The best activity showed compound 3g against Gram-negative microorganisms (0.21 μM) and reference strain Candida albicans (0.83 μM).
To know how normal human cells react to synthesized lead-compounds 3c, 3g, and 3f, we tested their toxicity on two human pseudonormal cell lines: human epidermal keratinocytes (HaCat) and normal murine fibroblasts (BALB/c 3T3) (Figure 4). In general, the HaCat cell line is more sensitive than the BALB/c 3T3 cell line to the action of our discovered compounds, but any reaches its IC50 value after 72h of compound exposure. The compound 3f shows the lowest toxicity effect on the pseudonormal cells.
According to obtained results, the tested compound 3g possesses a low ability to damage pseudonormal cells, had high antifungal activity, and revealed a promising area for further research.

3.3. Molecular and Pharmacokinetic Properties

The physical properties and the ADMET parameters of active compounds 3c, 3f, and 3g were calculated using the SwisAdme online server of the Swiss Institute of Bioinformatics [47]. As suggested by these data, all compounds are suited to Lipinski’s rule of five and may exhibit high gastrointestinal absorption and cross the blood–brain barrier (except 3g). The predicted lipophilicity of synthesized compounds given by log Po/w revealed good permeability and oral absorption through the cell membrane. Our tested compounds did not become p-glycoprotein substrates, suggesting that they could not be associated with the excretion of the drug. The negative skin permeability of the tested compounds may exhibit low skin permeation across the cell membrane. All the predictive data allow for the considering of compounds 3f, 3g, and 3c as prospective drug-like candidates in further in-depth studies (Table 3).

3.4. Molecular Docking Studies

Docking studies have revealed that the lead-compound 3g demonstrated good binding energy towards selected protein targets compared to the reference inhibitor N21 and ciprofloxacin (Table 4).
Molecule bonds to the active site of the protein by three hydrogen bonds with the LYS319 (1.92 Å), SER415 (1.87 Å), and ARG425 (3.09 Å). Summary binding energy increases owing to additional Pi–Pi T-shaped, Alkyl, and Pi-Alkyl hydrophobic interaction with the number of lipophilic amino acids ALA414, LEU416, PHE422, ILE 139. Additionally, LYS115, GLU157, and ASN138 form weak carbon–hydrogen bonds with two methoxy groups of 3g. However, the length of the molecule is quite small, and there is an absence of interaction with THR36, which is quite necessary for efficient MurD inhibition (Figure 5).
The docking results for compound 3g suggest that these compounds form key interactions with important residues at the binding site DNA gyrase (Figure 6). The compound makes a strong connection inside the active site of DNA gyrase owing to three hydrogen bonds with the SER1084 (1.81 Å), ASP437 (2.01Å), and GLY459 (2.15 Å). Additionally, the position of the molecule is stabilized by Pi–Pi-staked interaction between phenyl, 3H-thiazolo[4,5-b]pyridine cores and nucleotides DG9 and DT8. Moreover, the 3-methoxy group and the thiazole motif form Pi–Alkyl connections with ARG458 and DG9. Ciprofloxacin also forms a hydrogen bond with SER1084 and Pi–alkyl interaction with ARG458, and interactions with the amino acids, as mentioned above, are crucial for the expression of its antibacterial activity. Binding energies and inhibitory constant are equal to ciprofloxacin results, which suggest the good antibacterial potential of compound 3g.

4. Conclusions

Novel 5-methyl-7-phenyl-3H-thiazolo[4,5-b]pyridin-2-ones have been synthesized and characterized by spectral and elementary analyses. The synthesized compounds were assessed for their antimicrobial properties against clinical and reference strains and cytotoxicity capacities against HaCat and BALB/c 3T3 cell lines. The antimicrobial screening led to identifying the active compound 3g with the highest activity against Pseudomonas aeruginosa and Escherichia coli (MIC = 0.21 µM). Molecular and pharmacokinetic parameters of the promising active compounds showed satisfactory bioavailability and drug-likeness properties. Computational docking studies of compound 3g displaying the potent inhibitory effect suggest their good fitting in the active sites of MurD and DNA gyrase via different types of interactions.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/scipharm89040052/s1, Figures S1–S18: Copies of 1H, 13C NMR and LC-MS spectra of compounds 3a–g.

Author Contributions

Conceptualization, R.L.; Methodology and experimental work, A.L., Y.K., J.S., O.K., Y.S. and I.Y.; Data Analysis, A.L., Y.K., J.S., D.K. and R.L.; writing—review and editing, A.L., Y.K. and R.L.; Project administration and Supervision, R.L. All authors have read and agreed to the published version of the manuscript.

Funding

The research leading to these results has received funding from the Ministry of Health of Ukraine, under the project number: 0121U100690, and the National Research Foundation of Ukraine, under the project number: 2020.02/0035.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in this article.

Acknowledgments

This research was supported by the Danylo Halytsky Lviv National Medical University, which is gratefully acknowledged. A graphical abstract created with BioRender.com (accessed on 21 September 2021).

Conflicts of Interest

The authors declare no conflict of interest.

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Scipharm 89 00052 g001 550
Figure 1. Structures of biologically active fused pyridine derivatives.
Figure 1. Structures of biologically active fused pyridine derivatives.
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Figure 2. Background for target compounds synthesis.
Figure 2. Background for target compounds synthesis.
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Scipharm 89 00052 sch001 550
Scheme 1. Synthesis of 5-methyl-7-phenyl-3H-thiazolo[4,5-b]pyridin-2-ones 3a–g.
Scheme 1. Synthesis of 5-methyl-7-phenyl-3H-thiazolo[4,5-b]pyridin-2-ones 3a–g.
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Figure 3. In vitro antimicrobial activity of compounds 3a–g.
Figure 3. In vitro antimicrobial activity of compounds 3a–g.
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Figure 4. Effect of new thiazolopyridine derivatives with promising antimicrobial and antifungal profile on normal and pseudonormal cells in vitro. Effect of derivatives 3c, 3f and 3g on proliferative activity of HaCat and BALB/c 3T3 cells.
Figure 4. Effect of new thiazolopyridine derivatives with promising antimicrobial and antifungal profile on normal and pseudonormal cells in vitro. Effect of derivatives 3c, 3f and 3g on proliferative activity of HaCat and BALB/c 3T3 cells.
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Figure 5. Binding mode of 3g with MurD (PDB 2Y67).
Figure 5. Binding mode of 3g with MurD (PDB 2Y67).
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Figure 6. Binding mode of 3g with DNA gyrase (PDB 2XCT).
Figure 6. Binding mode of 3g with DNA gyrase (PDB 2XCT).
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Table
Table 1. In vitro antimicrobial activity of synthesized compounds (zone of growth inhibition at conc. 1 mg/mL after 24–48 h).
Table 1. In vitro antimicrobial activity of synthesized compounds (zone of growth inhibition at conc. 1 mg/mL after 24–48 h).
Type of SpeciesSpecies of Bacteria and FungiZone of Growth Inhibition
(mm ± SE)
3a3b3c3d3e3f3gDMSOVancomycinCiprofloxacinClotrimazole
1Gram-negative bacteriaReference strainsPseudomonas aeruginosa (ATCC 27853 (F-51))00000000007.0 ± 0.3 **9.0 ± 0.4 **00-35.0 ± 0.3-
2Escherichia coli (ATCC 25922)7.0 ± 0.25 **007.0 ± 0.3 **007.0 ± 0.2 **000000-42.0 ± 0.5-
3Raoultella terrigena (ATCC 33257)11.0 ± 0.4 **0011.6 ± 0.3 **000011.2 ± 0.4 **0000-30.0 ± 0.5-
4Clinical strainsPseudomonas aeruginosa N 79.2 ± 0.29.2 ± 0.29.2 ± 0.3 **9.2 ± 0.29.2 ± 0.29.5 ± 0.310.5 ± 0.4 *9.2 ± 0.2-20.0 ± 0.2-
5Escherichia coli N 3711.6 ± 0.25 **009.2 ± 0.2 **0000009.9 ± 0.2 **00-14.0 ± 0.4-
6Raoultella terrigena N112.0 ± 0.5 **0000000012.0 ± 0.3**0000-12.0 ± 0.3-
7Achromobacter xylosoxidans N 14710.0 ± 0.4 **8.0 ± 0.312.8 ± 0.3 **10.0 ± 0.4 **8.0 ± 0.38.0 ± 0.311.0 ± 0.2 **8.0 ± 0.2-15.0 ± 0.5-
8Citrobacter freundii N 27.7 ± 0.27.7 ± 0.29.0 ± 0.5 *10.8 ± 0.4 **7.7 ± 0.211.8 ± 0.4**11.8 ± 0.5 **7.7 ± 0.2-16.0 ± 0.3-
9Gram-positive bacteriaReference strainStaphylococcus aureus (ATCC 25923 (F-49))000011.2 ± 0.512.0 ± 0.30011.2 ± 0.30011.2 ± 0.432 ± 0.535.0 ± 0.5-
10Clinical strainsStaphylococcus aureus N 23000012.0 ± 0.312.2 ± 0.40011.4 ± 0.30011.6 ± 0.211.4 ± 0.39.0 ± 0.2-
11Kocuria marina N 133000012.2 ± 0.4 **000000000025.1 ± 0.48.0 ± 0.2-
12Micrococcus luteus N 13600000000000010.2 ± 0.4 **7.0 ± 0.312.0 ± 0.210.0 ± 0.2-
13FungiReference strainCandida. albicans (ATCC 885-653)14.4 ± 0.4 **14.5 ± 0.5 **009.6 ± 0.312.7 ± 0.4 **9.7 ± 0.312.2 ± 0.29.7 ± 0.2 **--18.0 ± 0.5
14Clinical strainsCandida albicans N 6000009.7 ± 0.39.2 ± 0.4 **0011.2 ± 0.5 **9.0 ± 0.3 **00--11.0 ± 0.3
15Candida kefyr N 6813.8 ± 0.1 **12.3 ± 0.49.8 ± 0.4 **14.5 ± 0.4 **14.9 ± 0.3 **14.6 ± 0.2 **14.7 ± 0.2 **12.5 ± 0.2--6.0 ± 0.2
16Saccharomyces cerevisiae N 62000012.5 ± 0.4 **8,0 ± 0.2 **008,0 ± 0.2 **0000--8.0 ± 0.2
Vancomycin 30 μg (inhibition zone 17–21 mm for S. aureus); Ciprofloxacin 5 μg (inhibition zone 25–33 mm for P. aeruginosa, 22–30 mm for S. aureus, 30–40 mm for E.coli); Clotrimazole 10 μg (inhibition zone 12–17 mm for Candida spp; * p < 0.05; ** p < 0.001, compare to DMSO; diameter of well 5.5 mm.
Table
Table 2. MIC value (μM) of compounds against bacterial species.
Table 2. MIC value (μM) of compounds against bacterial species.
μM
3a3c3f3gVancomycinCiprofloxacinClotrimazole
Pseudomonas aeruginosa N 7--1.560.21-1.81-
Escherichia coli N 371.840.96-0.21-1.51-
Raoultella terrigena N11.840.960.78--2.11-
Citrobacter freundii N 2-0.961.561.66-2.26-
Staphylococcus aureus N 23-0.96--4.163.02-
Micrococcus luteus N 136---1.662.774.53-
Candida. albicans (ATCC 885-653)1.840.961.560.83--1.16
Candida albicans N 601.841.921.561.66--2.9
‘-‘ not tested.
Table
Table 3. Physicochemical and pharmacokinetics properties of the active compounds 3f, 3g, and 3c.
Table 3. Physicochemical and pharmacokinetics properties of the active compounds 3f, 3g, and 3c.
3c3f3g
Physicochemical properties
Molecular weight260.29321.19302.35
Num. heavy atoms181821
Num. arom. heavy atoms151515
Num. rotatable bonds113
Num. H-bond acceptors324
Num. H-bond donors111
Molar Refractivity70.6078.3483.63
TPSA Ų73.9973.9992.45
Consensus log Po/w3.353.672.99
Lipinski’RuleYesYesYes
Pharmacokinetics
GI absorptionHighHighHigh
BBB permeantYesYesNo
p-gp substrateNoNoNo
Log Kp (SP) (cm/s) (skin permeation)−5.71−5.66−6.08
Bioavailability Score0.550.550.55
Table
Table 4. Docking results of 3g inside MurD (2Y67) and DNA gyrase (2XCT) active sites.
Table 4. Docking results of 3g inside MurD (2Y67) and DNA gyrase (2XCT) active sites.
MurD (2Y67)DNA Gyrase (2XCT)
COMPOUNDEstimated Free Energy of
Binding (kcal/mol)		Estimated Inhibitory
Constant, Ki (μM)		Estimated Free Energy of
Binding (kcal/mol)		Estimated Inhibitory
Constant, Ki
3g−6.3123.63 uM−8.28858.77 nM
Ciprofloxacin--−8.35756.11 nM
N21−6.0834.80 uM--
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Lozynskyi, A.; Konechnyi, Y.; Senkiv, J.; Yushyn, I.; Khyluk, D.; Karpenko, O.; Shepeta, Y.; Lesyk, R. Synthesis and Biological Activity Evaluation of Novel 5-Methyl-7-phenyl-3H-thiazolo[4,5-b]pyridin-2-ones. Sci. Pharm. 2021, 89, 52. https://doi.org/10.3390/scipharm89040052

AMA Style

Lozynskyi A, Konechnyi Y, Senkiv J, Yushyn I, Khyluk D, Karpenko O, Shepeta Y, Lesyk R. Synthesis and Biological Activity Evaluation of Novel 5-Methyl-7-phenyl-3H-thiazolo[4,5-b]pyridin-2-ones. Scientia Pharmaceutica. 2021; 89(4):52. https://doi.org/10.3390/scipharm89040052

Chicago/Turabian Style

Lozynskyi, Andrii, Yulian Konechnyi, Julia Senkiv, Ihor Yushyn, Dmytro Khyluk, Olexandr Karpenko, Yulia Shepeta, and Roman Lesyk. 2021. "Synthesis and Biological Activity Evaluation of Novel 5-Methyl-7-phenyl-3H-thiazolo[4,5-b]pyridin-2-ones" Scientia Pharmaceutica 89, no. 4: 52. https://doi.org/10.3390/scipharm89040052

APA Style

Lozynskyi, A., Konechnyi, Y., Senkiv, J., Yushyn, I., Khyluk, D., Karpenko, O., Shepeta, Y., & Lesyk, R. (2021). Synthesis and Biological Activity Evaluation of Novel 5-Methyl-7-phenyl-3H-thiazolo[4,5-b]pyridin-2-ones. Scientia Pharmaceutica, 89(4), 52. https://doi.org/10.3390/scipharm89040052

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