Synthesis and anticancer properties of N-(5-R-benzyl-1,3-thiazol- 2-yl)-2,5-dimethyl-3-furamides

© 2020 YE. Matiichuk et al.; Published by the Institute of Molecular Biology and Genetics, NAS of Ukraine on behalf of Biopolymers and Cell. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited UDC: 547.789.1+547.722


Materials and Methods
All starting materials were purchased from Merck and used without purification. NMR spectra were determined with Varian Mercury 400 (400 MHz) spectrometer, in DMSO-d 6 .
Melting points were determinated in open capillary tubes and are uncorrected. The purity of the compounds was checked by thin-layer chromatography performed with Merck Silica Gel 60 F254 aluminum sheets.
General procedure. To a solution of 0.01 mol of 2-aminothiazole 5a-g and 1 ml of triethylamine in 30 ml of anhydrous dioxane we ad ded under stirring 1.59g (0.01 mol) of 2,5-dimethyl-3-furoyl chloride 6. The mixture was left for 0.5 h and diluted with water, and the precipitate was filtered off, washed with water, and recrystallized from mixture alcohol -DMF.

Results and Discussion
according to the scheme. The diazonium salts were used as starting material. They react with acroleine under the Meerwein reaction condition [29] to form 3-aryl-2-chloropropanales [12]. These aldehydes were converted into 5-R-benzyl-thiazol-2-ylamines with high yields according to the previously reported synthetic protocols [12]. The acylation of 5-(R-benzyl)-1,3-thiazole-2-amines was carried out by the classical method using 2,5-dimethyl-3-furoyl chloride. The obtained amides 7a-g are high-melted substances of white or grey colour, poorly soluble in non-polar solvents, good in DMSO and DMF.
The structure of synthesized compounds was confirmed by 1 H NMR and microanalyses. In [the] 1 H NMR spectra, the signals for the protons of all the structural units were observed in their characteristic ranges. The protons of thiazole and furan rings were recorded as singlet at δ 7.24-7.27 ppm and 6.80-6.81ppm respectively. H-N amide protons appeared as a singlet at δ11.88-11.91 ppm and methylene groups at 4.00-4.08 ppm. Two other singlets at δ 2.49 and 2.22 ppm indicated methyl groups of furan rings.
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. The primary anticancer assay was performed at approximately sixty human tumor cell lines panel derived from nine neoplastic diseases, in accordance with the protocol of the Drug Evaluation Branch, National Cancer Institute, Bethesda [30][31][32][33]. The tested compounds were added to the culture at a single concentration (10 -5 M)  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.
The screening results are shown in Table 1

Scheme. Synthesis of N-(5-R-benzyl-1,3-thiazol-2-yl)-2,5-dimethyl-3-furamides 7a-g.
Finally, compound 7g was selected for an advanced assay against a panel of approximately sixty tumor cell lines at 10-fold dilutions of five concentrations (100 µM, 10 µM, 1.0 µM, 0.1 µM and 0.01 µM) ( Table 2). The percentage growth was evaluated spectropho-tometrically versus controls not treated with the test agents after 48-h exposure using the SRB protein assay to estimate the cell viability or growth. The dose-response parameters were calculated for each cell line: GI 50 -molar concentration of the compound leading to  Table 2). The most sensitive line was T-47D  The selectivity index (SI) obtained by dividing the full panel MG-MID (μM) of the compound 7g by its individual subpanel MG-MID (μM) was considered as a measure of compound's selectivity.The value between 3 and 6 refers to moderate selectivity. The index SI greater than 6 indicates a high selectivity toward the corresponding cell line, whereas the compounds meeting neither of the criteria are rated as non-selective [34]. In this context, the active compound 7g does not demonstrate any selectivity toward all tested cell lines (Table 3). Table 4 demonstrates that the tested compound 7g is effective against all of the cell lines, as it is shown by the full panel meangraph. MG-MID (µM) values for 7g are less than those for 5-fluorouracyl, curcumin and cisplatin when tested in the same manner.

Conclusions
A series of novel N-(5-R-benzyl-1,3-thiazol-2-yl)-2,5-dimethylfuran-3-carboxamides were synthesized and their anticancer activity was investigated. The compounds with significant levels of anticancer activity towards the selected cancer cell lines have been found and may be used for the further optimization.