Synthesis and anticancer properties of 5-(1H-benzoimidazol-2-ylmethylene)-4-oxo-2-thioxothiazolidin-3-ylcarboxilic acids

Volodymyr  Horishny; Taras Chaban; Vasyl  Matiychuk

doi:10.3897/pharmacia.68.e49224

Volodymyr Horishny^‡, Taras Chaban^‡, Vasyl Matiychuk^§

‡ Danylo Halytsky Lviv National Medical University, Lviv, Ukraine

§ Ivan Franko National University of Lviv, Lviv, Ukraine

Corresponding author: Vasyl Matiychuk ( v_matiychuk@ukr.net )

Academic editor: Georgi Momekov

This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation: Horishny V, Chaban T, Matiychuk V (2021) Synthesis and anticancer properties of 5-(1 H-benzoimidazol-2-ylmethylene)-4-oxo-2-thioxothiazolidin-3-ylcarboxilic acids. Pharmacia 68(1): 195-200. https://doi.org/10.3897/pharmacia.68.e49224

Abstract

The reaction of 1H-benzoimidazole-2-carbaldehyde with 4-oxo-2-thioxothiazolidin-3-ylcarboxilic acids was studied and the combinatorial library of 5-(1H-benzoimidazol-2-ylmethylene)-4-oxo-2-thioxothiazolidin-3-ylcarboxilic acids has been prepared. The structures of target compounds 8a-f, 9 and 10a, b were confirmed by using ¹H NMR spectroscopy and elemental analysis. The synthesized compounds were selected by the National Cancer Institute (NCI) Developmental Therapeutic Program for the in vitro cell line screening to investigate their anticancer activity. The tested compounds displayed a weak to medium anticancer activity. The most sensitive cell lines turned out to be SNB-75 of CNS Cancer (GP = 74.84–85.73%) and UO-31, Renal cancer (GP = 71.53–82.16%) and to compound 10a K-562 Leukemia cell lines (GP = 57.14).

Graphical abstract

Keywords

organic synthesis, 5-(1H-benzoimidazol-2-ylmethylene)-4-oxo-2-thioxothiazolidin-3-ylcarboxilic acids, anticancer properties

Introduction

Benzimidazoles and its derivatives are an important group of heterocyclic compounds that show a wide range of pharmacological properties such as antitumor, antimicrobial, antihypertensive, antiviral, antiulcer, anticonvulsant, antiinflammatory activities. Their widespread use as scaffolds in medicinal chemistry establishes this moiety as a member of the class of privileged structures (Kaur et al. 2014; Arulmurugan et al. 2015; Salahuddin et al. 2017).

On the other hand a detailed study of rhodanine (2-thioxo-4-thiazolidone) derivatives has made it possible to identify a lot of highly active agents with a wide range of biological activity. Among the 5-arylidenerhodanines, a lot of lead- compounds that possess various activities, including antimicrobial, antituberculous, antiviral, antidiabetic, anti-inflammatory, antitumor, anticonvulsant activities have been also found. At the present stage of development of medical chemistry, the rhodanine motif is considered to be also privileged (Tomasić and Masic 2009; Kaminskyy et al. 2009, 2017a; Kaminskyy et al. 2017b).

These diverse biological applications of benzimidazole and rhodanine compounds have motivated new efforts in search for novel their hybrids derivatives with improved biological activity and diverse applications in pharmaceutical industry.

Experimental part

Materials and methods

All chemicals were of analytical grade and commercially available. All reagents and solvents were used without further purification and drying. All the melting points were determined in an open capillary and are uncorrected.¹H- spectra were recorded on a Varian Mercury 400 (400 MHz for ¹H) instrument with TMS or deuterated solvent as an internal reference. Satisfactory elemental analyses were determined on a Elementar Vario L cube instrument (C±0.17, H±0.21, N±0.19).

Chemistry

2-Dichloromethyl-1H-benzoimidazole hydrochloride (3) . 0.2 Mol benzene-1,2-diamine, 0.26 mol dichloroacetic acid in 180 ml 20% hydrochloric acid were refluxed for 20 hours. Cooled to 0 °C, the precipitated of -dichloromethyl-1H-benzoimidazole hydrochloride was filtered off and washed with cold 20% hydrochloric acid and water. Yield 35g (74%). The obtained dichloromethyl-1H-benzoimidazole hydrochloride was used without further purification.

1H-Benzoimidazole-2-carbaldehyde (4) . 0,14 Mol of dichloromethyl-1H-benzoimidazole hydrochloride та 0,7 mole sodium acetate water 300 ml water stirred for 2 hours at 90–95 ºС. Cooled to room temperature. The precipitated of 1H-benzoimidazole-2-carbaldehyde was filtered off and washed with water, methanol and diethyl ether, dried and recrystallize from DMF. Yield 18,1г (89%), m. p. 235°С.

General procedure of the synthesis 5-(1H-benzoimidazol-2-ylmethylene)-4-oxo-2-thioxothiazolidin-3-ylcarboxilic acids 8-10. The solution of 3 mmol 4-oxo-2-thioxothiazolidin-3-ylcarboxilic acids, 3.6 mmol 1H-benzoimidazole-2-carbaldehyde and 3 mmol anhydrous sodium acetate in 7 ml acetic acid was refluxed for 1 hours. Cooled to room temperature. The precipitated was filtered off and washed with acetic acids and water, dried and recrystallize from acetic acid or acetic acid-DMF.

[5-(1H-Benzoimidazol-2-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl]acetic acid (8a). Yield 77%; m.p. = 272 °C decomp. ¹H NMR (400 MHz, DMSO-d₆) d 13.49 (s, 1H, COOH), 13.16 (s, 1H, NH), 7.80 (d, J = 7.8 Hz, 1H, benzoimidazole), 7.68 (s, 1H, CH=), 7.65 (d, J = 7.7 Hz, 1H, benzoimidazole), 7.33 (dt, J = 15.3, 6.7 Hz, 2H, benzoimidazole), 4.70 (s, 2H, CH₂). Anal. Calculated for C₁₃H₉N₃O₃S₂ %: C, 48.89; H, 2.84; N, 13.16. Found %: C, 48.70; H, 2.78; N, 13.21.

2-[5-(1H-Benzoimidazol-2-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl]-3-methylbutyric acid (8b). Yield 94%; m.p. = 260 °C decomp. ¹H NMR (400 MHz, d DMSO-d₆) d 13.26 (s, 1H, COOH), 13.20 (s, 1H, NH), 7.80 (d, J = 7.8 Hz, 1H, benzoimidazole), 7.67 (s, 1H, CH=), 7.65 (d, J = 7.6 Hz, 1H, benzoimidazole), 7.38–7.27 (m, 2H, benzoimidazole), 5.19 (d, J = 8.6 Hz, 1H, CH), 2.72 (dt, J = 20.8, 10.4 Hz, 1H, CH), 1.20 (d, J = 6.5 Hz, 3H, CH₃), 0.76 (d, J = 6.9 Hz, 3H, CH₃). Anal. Calculated for C₁₆H₁₅N₃O₃S₂ %: C, 53.17; H, 4.18; N, 11.63. Found %: C, 53.18; H, 4.25; N, 11.55.

2-[5-(1H-Benzoimidazol-2-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl]-4-methylpentanoic acid (8c). Yield 99%; m.p. = 244 °C decomp. ¹H NMR (400 MHz, DMSO-d₆) d 13.36 (s, 1H, COOH), 13.18 (s, 1H, NH), 7.80 (d, J = 7.4 Hz, 1H, benzoimidazole), 7.64 (s, 2H benzoimidazole + CH=), 7.38–7.27 (m, 2H, benzoimidazole), 5.59 (s, 1H, CH), 2.18 (d, J = 9.6 Hz, 1H, CH), 2.02 (ddd, J = 13.0, 8.5, 4.3 Hz, 1H, CH), 1.50 (s, 1H, CH), 0.92 (d, J = 6.5 Hz, 3H, CH₃), 0.87 (d, J = 6.6 Hz, 3H, CH₃). Anal. Calculated for C₁₇H₁₇N₃O₃S₂ %: C, 54.38; H, 4.56; N, 11.19. Found %: C, 54.66; H, 4.62; N, 11.29.

2-[5-(1H-Benzoimidazol-2-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-3-methylpentanoic acid (8d). Yield 66%; m.p. = 259 °C decomp. ¹H NMR (400 MHz DMSO-d₆) d 13.25 (s, 1H, COOH), 13.20 (s, 1H, NH), 7.80 (d, J = 7.9 Hz, 1H, benzoimidazole), 7.66 (s, 1H, benzoimidazole), 7.64 (s, 1H, CH=), 7.33 (dt, J = 15.0, 6.9 Hz, 2H. benzoimidazole), 5.24 (d, J = 9.0 Hz, 1H, CH), 1.25 (s, 1H, CH), 1.16 (d, J = 6.4 Hz, 3H, CH₃), 0.96 (s, 1H, CH), 0.80 (t, J = 7.3 Hz, 3H, CH₃). Anal. Calculated for C₁₇H₁₇N₃O₃S₂ %: C, 54.38; H, 4.56; N, 11.19. Found %: C, 54.57; H, 4.44; N, 11.33.

2-[5-(1H-Benzoimidazol-2-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-3-phenylpropionic acid (8e). Yield 83%; m.p. = 258 °C decomp. ¹H NMR (400 MHz, DMSO-d₆) d 13.49 (s, 1H, COOH), 13.15 (s, 1H, NH), 7.76 (d, J = 7.9 Hz, 1H, benzoimidazole), 7.64 (d, J = 7.9 Hz, 1H, benzoimidazole), 7.60 (s, 1H, CH=), 7.32 (dt, J = 15.2, 6.8 Hz, 2H, benzoimidazole), 7.24–7.12 (m, 5H, Ph), 5.88 (s, 1H, CH), 3.51 (d, J = 5.6 Hz, 2H, CH₂). Anal. Calculated for C₂₀H₁₅N₃O₃S₂ %: C, 58.66; H, 3.69; N, 10.26. Found %: C, 58.74; H, 3.55; N, 10.25.

2-[5-(1H-Benzoimidazol-2-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl]-3-(4-hydroxy-phenyl)propionic acid (8f). Yield 99%; m.p. = 278 °C decomp. ¹H NMR (400 MHz, DMSO-d₆) d 13.18 (s, 1H, NH), 9.20 (s, 1H, OH), 7.77 (d, J = 7.9 Hz, 1H, benzoimidazole), 7.64 (d, J = 7.7 Hz, 1H, benzoimidazole), 7.60 (s, 1H, CH=), 7.32 (dt, J = 15.2, 7.0 Hz, 2H, benzoimidazole), 6.93 (d, J = 8.3 Hz, 2H, C₆H₄OH), 6.57 (d, J = 8.4 Hz, 2H, C₆H₄OH), 5.78 (s, 1H, CH), 3.36 (s, 2H, CH₂). Anal. Calculated for C₂₀H₁₅N₃O₃S₂ %: C, 56.46; H, 3.55; N, 9.88. Found %: C, 56.14; H, 3.41; N, 9.61.

3-[5-(1H-Benzoimidazol-2-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl]propionic acid (9). Yield 95%; m.p. = 262 °C decomp. ¹H NMR (400 MHz, DMSO-d₆) d 13.08 (s, 1H, NH), 12.44 (s, 1H, COOH), 7.78 (d, J = 7.8 Hz, 1H, benzoimidazole), 7.64 (s, 1H, CH=), 7.61 (s, 1H, benzoimidazole), 7.37–7.26 (m, 2H, benzoimidazole), 4.24 (t, J = 7.7 Hz, 2H, CH₂), 2.65 (t, J = 7.7 Hz, 2H, CH₂). Anal. Calculated for C₁₄H₁₁N₃O₃S₂ %: C, 50.44; H, 3.33; N, 12.60. Found %: C, 50.16; H, 3.29; N, 12.48.

3-[5-(1H-Benzoimidazol-2-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl]benzoic acid (10a). Yield 77%; m.p. = >280 °C. ¹H NMR (400 MHz, DMSO-d₆) d 13.12 (s, 1H, NH), 8.08 (dd, J = 5.8, 2.7 Hz, 1H, Ar), 8.04 (s, 1H, Ar), 7.83 (d, J = 7.6 Hz, 1H, benzoimidazole), 7.73–7.69 (m, 2H, Ar), 7.67 (d, J = 6.4 Hz, 1H, benzoimidazole), 7.65 (s, 1H, CH=), 7.38–7.28 (m, 2H, benzoimidazole). Anal. Calculated for C₁₈H₁₁N₃O₃S₂ %: C, 56.68; H, 2.91; N, 11.02. Found %: C, 56.44; H, 3.12; N, 11.25.

5-[5-(1H-Benzoimidazol-2-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl]-2-hydroxybenzoic acid (10b). Yield 90%; m.p. = 279 °C decomp. ¹H NMR (400 MHz, DMSO-d₆) d 13.10 (s, 1H), 7.88 (s, 1H, benzoimidazole), 7.64 (s, 1H, CH=), 7.61 (s, 1H, benzoimidazole) 7.56 (d, J = 8.9 Hz, 1H, Ar), 7.34 (s, 2H, benzoimidazole), 7.12 (d, J = 8.8 Hz, 1H, Ar). Anal. Calculated for C₁₈H₁₁N₃O₄S₂ %: C, 54.40; H, 2.79; N, 10.57. Found %: C, 54.02; H, 2.84; N, 10.66.

Pharmacology

Primary anticancer assay was performed at approximatelysixty human tumor cell lines panel derived from nine neoplasticdiseases, in accordance with the protocol of the Drug Evaluation Branch, National Cancer Institute, Bethesda (Monks et al. 1991; Boyd et al. 1995; Shoemaker 2006). Tested compounds were added to the culture at a single concentration (10^-5M) and the cultures were incubated for 48 h. End pointdeterminations were made with a protein binding dye, sulforhodamine B (SRB). Results for each tested compound were reported as the percent of growth of the treated cells when compared to the untreated control cells. The percentage growth was evaluated spectrophotometrically versus controls not treated with test agents.

Using the absorbance measurements [time zero, (Tz); control growth in the absence of drug, (C); and test growth in the presence of drug at the mentioned concentration (Ti)], the percentage growth inhibition was as:

[(Ti- Tz) / (C - Tz)] × 100 whenTi³Tz,

[(Ti - Tz) / Tz] × 100 whenTi<Tz.

spectrophotometrically versus controls not treated with the test agents.

Results and discussion

Chemistry

Continuing our works (Zimenkovskii et al. 2006; Matiichuk et al. 2008; Obushak et al. 2009; Pokhodylo et al. 2009a, b; Zubkov et al. 2010; Klenina et al. 2013, 2017; Chaban et al. 2014, 2016, 2017a, b, 2018a, b, 2019a, b; Lozynska et al. 2015; Zelisko et al. 2015; Tymoshuk et al. 2019), on the synthesis and study of biological activity of azole derivatives we prepare combinatorial libraries of [5-(1H-benzoimidazol-2-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-ylcarboxilc and investigated their anticancer activities. We have been developed the method of the synthesis of 1H-benzoimidazole-2-carbaldehyde (4). At first stage orthophenylenediamine (1) we condensed with dichloroacetic acid (2). As result 2-dichloromethyl-1H-benzoimidazole (3) was prepared. 2-dichloromethyl group under go hydrolysis by aqueous solution sodium acetate to form target 1H-benzoimidazole-2-carbaldehyde (4) (Scheme 1).

Scheme 1.

Synthesis of 1H-benzoimidazole-2-carbaldehyde.

We investigated the reaction of 1H-benzoimidazole-2-carbaldehyde with 4-oxo-2-thioxothiazolidin-3-ylcarboxilic acids. We found that the optimal condition for the condensation is boiling acetic acid in presence of sodium acetate as a catalyst. As the result a series of novel derivatives [5-(1H-benzoimidazol-2-ylmethylene)-4-oxo-2-thioxo-thiazolidine-3-ylcarboxilc acid 8-10 were prepared (Scheme 2). The yields of the reaction products were 66–99%. The resulting 5-(benzimidazolidine-2)rhodanine-3-carboxylic acids 8-10 are powders of yellow-orange, orange or orange-red color, well soluble in DMF, DMSO, boiling acetic acids, insoluble in alcohol, benzene, ethers and water.

Scheme 2.

Synthesis of 5-(1H-benzoimidazol-2-ylmethylene)-4-oxo-2-thioxothiazolidin -3-ylcarboxilic acids.

The structure of compounds 8-10 was confirmed by ¹H NMR spectroscopy. In ¹H NMR spectra, signals for the protons of all the structural units were observed in their characteristic ranges. The chemical shift for the methylidene group is insignificantly displaced in a weak magnetic field, δ = 7,60–7,68 ppm and clearly indicated that only Z-isomers were obtained. NH proton of benzoimidazole ring shows the singlet at 13,08–13,20 ppm. Due to steric hindrances, the rotation around the N-C bond in the position 3 in compound 8b is difficult and the methyl groups are not equivalent. The protons of methyl groups appear as two doublets at 0.76 and 1.20 ppm. Similar effects are observed in the case of compound 8c.

Anticancer activity

The synthesized compounds were selected by the National Cancer Institute (NCI) Developmental Therapeutic Program (www.dtp.nci.nih.gov) for the in vitro cell line screening to investigate their anticancer activity. Anticancer assays were performed according to the NCI protocol, which is described elsewhere (Monks et al. 1991; Boyd et al. 1995; Boyd et al. 1997; Shoemaker et al. 2006). The human tumor cell lines were derived from nine different cancer types: leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate and breast cancers. Initially, a single high concentration was used (10 μM) in the full NCI 60-cell panel. In the screening protocol, each cell line was inoculated and preincubated for 24–48 h on a microtiter plate. Then test substances were added to the plate and the culture was incubated for further 48 h. End point determiations were made with a protein binding dye, sulforhodamine B. Results for each test agent were reported as the percent growth of the treated cells when compared to the untreated control cells and are shown in Тable 1.

The tested compounds displayed a weak to medium anticancer activity. The most sensitive cell lines turned out to be SNB-75 of CNS Cancer (GP = 74.84–85.73%) and UO-31, Renal cancer (GP = 71.53–82.16%) and to compound 10a K-562 Leukemia cell lines (GP = 57.14). It should also be noticed that all compounds stimulate the growing of CCRF-CEM and SR Leukemia cell lines.

Table 1.

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CSV

XLSX

Cytotoxic activity of the tested compounds in the concentration 10⁻⁵ M against 60 cancer cell lines.

Test compounds	Mitotic activity 60 cancer cell lines GP %		Most sensitive cell line (cancer line/type) GP, %
Test compounds	Average growth, %	Range of growth, %	Most sensitive cell line (cancer line/type) GP, %
8a	98.93	74.37–143.90	SNB-75 (CNS Cancer) 83.89
			MALME-3M (Melanoma) 81.63
			UO-31 (Renal Cancer) 74.37
8b	100.30	76.42–122.20	SNB-75 (CNS Cancer) 83.70
8b	100.30	76.42–122.20	UO-31 (Renal Cancer) 76.42
8c	100.49	78.88–127.16	SNB-75 (CNS Cancer) 78.88
8c	100.49	78.88–127.16	UO-31 (Renal Cancer) 80.50
8d	101.36	73.79–154.33	SNB-75 (CNS Cancer) 85.73
8d	101.36	73.79–154.33	UO-31 (Renal Cancer) 73.79
8e	101.23	81.40–136.54	SNB-75 (CNS Cancer) 81.40
8e	101.23	81.40–136.54	UO-31 (Renal Cancer) 82.16
8f	101.06	71.53–127.99	SNB-75 (CNS Cancer) 78.08
			CAKI-1 (Renal Cancer) 83.37
			UO-31 (Renal Cancer) 71.53
9	98.79	73.24–123.19	SNB-75 (CNS Cancer) 75.43
9	98.79	73.24–123.19	UO-31 (CNS Cancer) 73.24
10a	99.38	57.14–111.51	K-562 (Leukemia) 57.14
			SNB-75 (CNS Cancer) 74.84
			UO-31 (Renal Cancer) 76.84
10b	101.36	73.79–154.33	SNB-75 (CNS Cancer) 85.73
10b	101.36	73.79–154.33	UO-31 (Renal Cancer) 73.79

Conclusions

In our work, we presented an efﬁcient synthesis and anticancer activity evaluation of some 5-(1H-benzoimidazol-2-ylmethylene)-4-oxo-2-thioxothiazolidin-3-ylcarboxilic acids. First, anticancer activity was detected among the compounds tested. Further optimization of the structure to improve their activities is currently in progress.

References

Arulmurugan S, Kavitha HP, Sathishkumar S, Rajaram A (2015) Biologically Active Benzimidazole Derivatives. Mini-Reviews in Organic Chemistry 12(2): 178–195. https://doi.org/10.2174/1570193X1202150225153403

Boyd MR, Paull KD (1995) Some practical considerations and applications of the national cancer institute in vitro anticancer drug discovery screen. Drug Development Research 34: 91–109. https://doi.org/10.1002/ddr.430340203

Boyd MR, Teicher BA (1997) Cancer Drug Discovery and Development. Humana Press. Chap 2: 23–43.

Chaban T, Klenina O, Drapak I, Ogurtsov V, Chaban I, Novikov V (2014) Synthesis of some novel thiazolo[4,5-b]pyridines and their tuberculostatic activity evaluation. Chemistry and Chemical Technology 89: 287–292. https://doi.org/10.23939/chcht08.03.287

Chaban TI, Klenina OV, Zimenkovsky BS, Chaban IG, Ogurtsov VV, Shelepeten LS (2016) Synthesis of novel thiazolo[4,5-b]pyridines as potential biologically active substances. Der Pharma Chemica 8(19): 534–542. https://www.derpharmachemica.com/pharma-chemica/synthesis-of-novel-thiazolo-45b-pyridines-as-potential-biologically-active-substances.pdf

Chaban Z, Harkov S, Chaban T, Klenina O, Ogurtsov V, Chaban I (2017a) Recent advances in synthesis and biological activity evaluation of condensed thiazoloquinazolines: A review. Pharmacia 64(3): 52–66. http://bsphs.org/?magasine=recent-advances-in-synthesis-and-biological-activity-evaluation-of-condensed-thiazoloquinazolines-a-review

Chaban T, Klenina O, Harkov S, Ogurtsov V, Chaban I, Nektegaev I (2017b) Synthesis of some new N³ substituted 6-phenylazo-3Н-thiazolo[4,5-b]pyridin-2-ones as possible anti-inflammatory agents. Pharmacia 64(4): 16–30. http://bsphs.org/?magasine=synthesis-of-some-new-n3-substituted-6-phenylazo-3%d0%bd-thiazolo45-bpyridin-2-ones-as-possible-anti-inflammatory-agents

Chaban T, Klenina O, Chaban I, Ogurtsov V, Harkov S, Lelyukh M (2018a) Thiazolo[5,4-d]pyrimidines and thiazolo[4,5-d]pyrimidines: A review on synthesis and pharmacological importance of their derivatives. Pharmacia 65(2): 54–70. http://bsphs.org/?magasine=thiazolo54-dpyrimidines-and-thiazolo45-dpyrimidines-a-review-on-synthesis-and-pharmacological-importance-of-their-derivatives

Chaban T, Matiychuk V, Ogurtsov V, Chaban I, Harkov S, Nektegaev I (2018b) Synthesis and biological activity of some novel derivatives 5,7-dimethyl-6-phenylazo-3Н-thiazolo[4,5-b]pyridine-2-one. Pharmacia 65(4): 51–62. http://bsphs.org/?magasine=synthesis-and-biological-activity-of-some-novel-derivatives-57-dimethyl-6-phenylazo-3%d0%bd-thiazolo45-bpyridine-2-one

Chaban TI, Ogurtsov VV, Matiychuk VS, Chaban IG, Demchuk IL, Nektegayev IA (2019a) Synthesis, anti-inflammatory and antioxidant activities of novel 3H-thiazolo[4,5-b]pyridines. Acta Chimica Slovenica 66: 103–111. https://doi.org/10.17344/acsi.2018.4570

Chaban T, Ogurtsov V, Chaban I, Myrko I, Harkov S, Leluykh M (2019b) Synthesis of some new 4-iminothiazolidine-2-ones as possible antioxidants agents. Pharmacia 66(1): 27–32. https://doi.org/10.3897/pharmacia.66.e35131

Kaminskyy D, Zimenkovsky B, Lesyk R (2009) Synthesis and in vitro anticancer activity of 2, 4-azolidinedione-acetic acids derivatives. European journal of medicinal chemistry 44(9): 3627–3636. https://doi.org/10.1016/j.ejmech.2009.02.023

Kaminskyy D, Kryshchyshyn A, Lesyk R (2017a) Recent developments with rhodanine as a scaffold for drug discovery. Expert Opin. Drug Discov. 12(12): 1233–1252. https://doi.org/10.1080/17460441.2017.1388370

Kaminskyy D, Kryshchyshyn A, Lesyk R (2017b) 5-Ene-4-thiazolidinones. An efﬁcient tool in medicinal chemistry. European Journal of Medicinal Chemistry 140: 542–594. https://doi.org/10.3390/scipharm86020026

Kaur G, Kaur M, Silakari O (2014) Benzimidazoles: an ideal privileged drug scaffold for the design of multitargeted anti-inflammatory ligands. Mini-Reviews in Medicinal Chemistry 14(9): 747–767. https://doi.org/10.2174/1389557514666140820120518

Klenina O, Drapak I, Chaban T, Ogurtsov V, Chaban I, Golos I (2013) QSAR studies of some thiazolo[4,5-b]pyridines as novel antioxidant agents: enhancement of activity by some molecular structure parameters. Chemistry and Chemical Technology 7: 397–404. https://doi.org/10.23939/chcht07.04.397

Klenina O, Chaban T, Zimenkovsky B, Harkov S, Ogurtsov V, Chaban I, Myrko I (2017) Qsar modeling for antioxidant activity of novel N³ substituted 5,7-dimethyl-3Н-thiazolo[4,5-b]pyridin-2-ones. Pharmacia 64(4): 49–71. http://bsphs.org/?magasine=qsar-modeling-for-antioxidant-activity-of-novel-n3-substituted-57-dimethyl-3%d0%bd-thiazolo45-bpyridin-2-ones

Lozynska L, Tymoshuk O, Chaban T (2015) Spectrophotometric studies of 4-[n’-(4-imino-2-oxo-thiazolidin-5-ylidene)-hydrazino]-benzenesulfonic acid as a reagent for the determination of Palladium. Acta Chimica Slovenica 62: 159–167. https://doi.org/10.17344/acsi.2014.866

Matiichuk VS, Potopnyk MA, Obushak ND (2008) Molecular design of pyrazolo[3,4-d]pyridazines. Russian Journal of Organic Chemistry 44(9): 1352–1361. https://doi.org/10.1134/S1070428008090182

Monks A, Scudiero D, Skehan P, Shoemaker R, Paull K, Vistica D, Hose C, Langley J, Cronise P, Vaigro-Wolff Monks A (1991) Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. Journal of the National Cancer Institute 83: 757–766. https://doi.org/10.1093/jnci/83.11.757

Obushak ND, Lesyuk AI, Gorak YI, Matiichuk VS (2009) Mechanism of Meerwein arylation of furan derivatives. Russian Journal of Organic Chemistry 45(9): 1375–1381. https://doi.org/10.1134/S1070428009090103

Pokhodylo NT, Matiychuk VS, Obushak MD (2009a) Synthesis of ethyl 4,5-disubstituted 2-azido-3-thiophenecarboxylates and use in the synthesis of thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidin-5(4H)-ones Tetrahedron 65(13): 2678–2683. https://doi.org/10.1016/j.tet.2009.01.086

Pokhodylo NT, Savka RD, Matiichuk VS, Obushak ND (2009b) Synthesis and selected transformations of 1-(5-methyl-1-aryl-1H-1,2,3- triazol-4-yl)ethanones and 1-[4-(4-R-5-methyl-1H-1,2,3-triazol-1-yl)phenyl] ethanones. Russian Journal of General Chemistry 79(2): 309–314. https://doi.org/10.1134/S1070363209020248

Salahuddin A, Shaharyar M, Mazumder A (2017) Benzimidazoles: A biologically active compounds. Arabian Journal of Chemistry 10: 157–173. https://doi.org/10.1016/j.arabjc.2012.07.017

Shoemaker RH (2006) The NCI60 human tumour cell line anticancer drug screen. Nature Reviews Cancer 6: 813–823. https://doi.org/10.1038/nrc1951

Tomasić T, Masic LP (2009) Rhodanine as a privileged scaffold in drug discovery. Current Medicinal Chemistry 16(13): 1596–1629. https://doi.org/10.2174/092986709788186200

Tymoshuk O, Oleksiv L, Khvalbota L, Chaban T, Patsay I (2019) Spectrophotometric determination of ru(iv) using 5-hydroxyimino-4-imino-1,3-thiazolidin-2-one as a novel analytical reagent. Acta Chimica Slovenica 66: 62–69. https://doi.org/10.17344/acsi.2018.4448

Zelisko N, Atamanyuk D, Ostapiuk Y, Bryhas A, Matiychuk V, Gzella A, Lesyk R (2015) Synthesis of fused thiopyrano[2,3-d][1,3]thiazoles via hetero-Diels-Alder reaction related tandem and domino processes. Tetrahedron 71(50): 9501–9508. https://doi.org/10.1016/j.tet.2015.10.019

Zimenkovskii BS, Kutsyk RV, Lesyk RB, Matyichuk VS, Obushak ND, Klyufinska TI (2006) Synthesis and antimicrobial activity of 2,4-dioxothiazolidine-5-acetic acid amides. Pharmaceutical Chemistry Journal 40(6): 303–306. https://doi.org/10.7124/bc.000971

Zubkov FI, Ershova JD, Zaytsev VP, Obushak MD, Matiychuk VS, Sokolova EA, Khrustalev VN, Varlamov AV (2010) The first example of an intramolecular Diels-Alder furan (IMDAF) reaction of iminium salts and its application in a short and simple synthesis of the isoindolo[1, 2-a]isoquinoline core of the jamtine and hirsutine alkaloids. Tetrahedron Letters 51(52): 6822–6824. https://doi.org/10.1016/j.tetlet.2010.10.046