INTRODUCTION:

Cancer diseases are one of the most urgent medical, biological and social problems of the present. Oncologic pathology causes up to 8% of all deaths and is inferior only to cardiovascular diseases. Despite of significant success in using chemotherapy for malignant tumors, many types of cancer remain incurable, the available anti-cancer drug range is insufficient. Therefore, the search for new organic compounds that possess anticancer activity is an urgent task of the present.

Heterocyclic compounds with 3-furan-2-ylacrylonitrile or thiazole fragment in the molecule are a well-known group of biologically active substances, which characterized by a variety of effects^1-15. The derivatives of 3-(5-aryl furan-2-yl) acrylonitrile have been studied much less. This class of compounds is reported for having antivira¹⁶, anti-TB^17,18, acetylcholinesterase^19,20and antitumor^21-23activity. In particular, the authors of the study²¹ identified 2-arylacrylonitrilepharmacophore with antitumor activity (structure I). By developing the data of the study, we made its modification by the replacing the aryl fragment with benzimidazole (structure II), benzothiazole (structure III) and 4-arylthiazole (structure IV) ring. This causes the appearance of additional donors and acceptors of hydrogen bond, which can facilitate ligand binding to the target.

In our previous work we have developed methods of synthesis of furane^22,23, pyrazole²⁴, thiazole^25-27, triazole²⁸derivatives based on using of diazonium salt as started reagents. The condensed compounds were also prepared^{22-24, 28-3}⁷. The advantage of the proposed method is that the synthesis of arendiazonium salt is very simple from aromatic amines that is abundantly available in the commercial market with low price. It means that variety of different substituents in organic molecules can be introduction. It is very important for purposes of medical chemistry. In this article we describe the synthesis and evolution of anticancer activity of new derivatives of 3-(5-arylfuran-2-yl)acrylonitrile

MATERIALS AND METHODS:

Materials.

All chemicals were of analytical grade and commercially available. All reagents and solvents were used without further purification and drying.

Chemistry.

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 obtained for new compounds (C±0.17, H±0.21, N±0.19).

The general method for the synthesis of 2-(1H-benzimidazol-2-yl) - and 2-benzthiazol-2-yl-3- (5-aryl furan-2-yl) acrylonitrile and 2-(4-arylhiazol-2-yl)-3-(5-p-aryl furan-2-yl)-acrylonitrile4a-c, 5a-c, 6a-с.The 0.01 mol of 5-arylfurfural 1a-d and 0.01mol of 1H-benzimidazol-2-yl) -2a or benzthiazol-2-ylacetonitrile 2b was dissolved in 20 ml of ethanol in the presence of 2 ml of piperidine. The flask was refluxed for 1 h. The precipitate formed, filtered off, washed with alcohol, and the product was purified by recrystallization from a mixture of ethanol-DMF.

2-(1H-Benzimidazol-2-yl)-3-[5-(4-chlorophenyl)furan-2-yl]-acrylonitrile (4а). Yield: 84 %; mp>250 ºС; ¹H NMR: δ_H=13.01 (s, 1H, NH), 8.14 (s, 1H, CH=), 7.94 (d, J = 7.0 Hz, 2H, С₆Н₄), 7.67 (d, J = 7.0 Hz, 2H, С₆Н₄), 7.53 (d, J = 7.0 Hz, 2H, benzimidazole), 7.41 (s, 1H, furane), 7.39 (s, 1H, furane), 7.24 (m, 2H, benzimidazole).Anal. calcd. forC₂₀H₁₂ClN₃O. С 69.47; Н 3.50; N 12.15;found: C 69.54; Н 3.55; N 12.26.

2-(1H-Benzimidazol-2-yl)-3-[5-(4-bromophenyl) furan-2-yl]-acrylonitrile(4b). Yield: 80 %; mp>250ºС; ¹H NMR: δ_H= 13.01 (s, 1H, NH), 8.14 (s, 1H, CH=), 7.86 (d, J = 7.9 Hz, 2H, С₆Н₄), 7.74 (d, J = 8.0 Hz, 2H, С₆Н₄), 7.60 (s, 2H, benzimidazole), 7.42 (s, 1H, furane), 7.39 (d, J = 2.5 Hz, 1H, furane), 7.24 (m, 2H, benzimidazole). Anal.calcd. for C₂₀H₁₂BrN₃O. С 61.56; Н 3.10; N 10.77; found: С 61.51; Н 3.14; N 10.83.

2-(1H-Benzimidazol-2-yl)-3-[5-(2,5-dichlorophenyl) furan-2-yl]acrylonitrile (4c). Yield: 85 %; mp>250ºС; ¹H NMR: δ_H= 13.02 (s, 1H, NH), 8.17 (s, 1H, CH=), 7.83 (d, 1H, J = 2.0 Hz, C₆H₃) 7.67 (d, 2H, J = 7.0 Hz, benzimidazole), 7.62 (d, 2H, J = 7.0 Hz, benzimidazole), 7.59 (d, 1H, J = 8.0 Hz, C₆H₃) 7,49 (1H, d.d, J = 8.0 і 2.0 Hz, С₆Н₃), 7.45 (s, 1H, furane), 7.42 (s, 1H, furane), 7.26 (m, 2H, benzimidazole). Anal. calcd. forC₂₀H₁₁Cl₂N₃O. C63.18; Н 2.92; N 11.05; found:С 63.24; Н 3.01; N 11.12.

2-Benzothiazol-2-yl-3-[5-(4-chlorophenyl)furan-2-yl]-acrylonitrile(5a).Yield: 79 %; mp>250 ºС; ¹H NMR: δ_H=8.21 (s, 1Н, СН), 8.14 (d, 1Н, J = 7.8 Hz, benzothiazole), 8.03 (d, 1Н, J = 7.8 Hz, benzothiazole), 7.92 (д, 2Н, J = 8.8 Hz, С₆Н₄), 7.59 (d, 2Н, J = 8.8 Hz, С₆Н₄), 7.56 (t, J = 7.8 Hz, 1Н, benzothiazole), 7.50 (d, 1Н, J = 3.9 Hz, furane), 7.47 (t, 1Н, J = 7.8 Hz, benzothiazole), 7.41 (d, 1Н, J = 3.9 Hz, furane).Anal.calcd. for C₂₀H₁₁ClN₂OS. С 66.21; Н 3.06; N 7.72; found: С 66.30; Н 3.11; N 7.81.

2-Benzothiazol-2-yl-3-[5-(2,5-dichlorophenyl)-furan-2-yl]-acrylonitrile (5b).Yield: 84 %; mp>250 ºС; ¹H NMR: δ_H= 8.24 (s, 1Н, СН=), 8.15 (d, 1Н, J = 7.8 Hz, benzothiazole), 8.06 (d, 1Н, J = 7.8 Hz, benzothiazole), 7.85 (s, 1H, C₆H₃), 7.59 (d, 1H, J = 8.0 Hz, C₆H₃); 7.56 (t, 1Н, J = 7.8 Hz, benzothiazole); 7.51 (d, 1H, J = 8.0 Hz, С₆Н₃), 7.47 (t, 1Н, J = 7.8 Hz, benzothiazole); 7.45 (s, 1H, furane), 7.42 (s, 1H, furane).Anal.calcd. forC₂₀H₁₀Cl₂N₂OS. С 60.47; Н 2.54; N 7.05; found: С 60.54; Н 2.6; N 7.11.

2-(4-Phenyl-thiazol-2-yl)-3-(5-p-tolylfuran-2-yl)-acrylonitrile (6a).Yield: 75 %; mp135-136ºС; ¹H NMR: δ_H= 8.22 (s, 1H,СН), 8.15 (s, 1Н, thiazole), 8.02 (d, J = 7.4 Hz, 2H, С₆Н₄), 7.82 (d, J = 7.6 Hz, 2H, С₆Н₄), 7.48 (t, J = 7.3 Hz, 2H, С₆Н₅), 7.42 (s, 1H, furane), 7.39 (s, 1H, furane), 7.32 (d, J = 7.7 Hz, 2H, С₆Н₅), 7.29 (s, 1H, С₆Н₅), 2.35 (s, 1H, СН₃).Anal.calcd. forC₂₃H₁₆N₂OS. С 74.98; Н 4.38; N 7.60; found: С 75.08; Н 4.44; N 7.55.

2-[4-(4-Fluoro-phenyl)-thiazol-2-yl]-3-[5-(3-trifluoromethyl-phenyl)-furan-2-yl]-acrylonitrile (6b).Yield: 84 %; mp213 -215 ºС; ¹H NMR: δ_H= 8.26 (s, 1H,СН), 8.23 (s, 1Н, thiazole), 8.20 (s, 1H,4-CF₃-С₆Н₄), 8.18 (s, 1Н, 3-CF₃-С₆Н₄), 8.06 (dd, J = 8.3, 5.6Hz, 2H, С₆Н₄), 7.75 (d, J = 7.6 Hz, 2H, С₆Н₄), 7.55 (d, J = 3.6 Hz, 1H,furane), 7.45 (d, J = 3.6 Hz, 1H,furane),7.31 (t, J = J 8.0 Hz, 2H,3-CF₃-С₆Н₄). Anal.calcd. for C₂₃H₁₂F₄N₂OS. С 62.73; Н 2.75; N 6.36; found: С 62.65; Н 2.80; N 6.26.

2-(4-Furan-2-yl-thiazol-2-yl)-3-(5-p-tolyl-furan-2-yl)-acrylonitrile(6c).Yield: 74 %; mp139-140 ºС; ¹H NMR: δ_H=8.10 (s, 1H,СН),7.91 (s, 1Н, thiazole),7.82 (d, J = 8.0Hz, 2H, С₆Н₄), 7.79 (s, 1H, furane), 7.43 (d, J = 3.6 Hz, 1H,furane), 7.33 (d, J = 7.9Hz, 2H, С₆Н₄), 7.29 (d, J = 3.6 Hz, 1H,furane), 6.89 (s, 1H, furane), 6.63 (s, 1H, furane),2.35 (s, 1H, СН₃).Anal.calcd. for C₂₁H₁₄N₂O₂S. С 70.37; Н 3.94; N 7.82; found: С 70.24; Н 3.88; N 7.77.

RESULTS AND DISCUSSION:

The synthesis of the target 2-(1H-benzoimidazol-2-yl)-3-(5-arylfuran-2-yl)-acrylonitrile4a-c, 2-benzothiazol-2-yl-3-(5-arylfuran-2-yl)-acrylonitrile 5a-c and 3-(5-arylfuran-2-yl)-2-(4-arylthiazol-2-yl)-acrylonitrile6a-c was carried out using the Knoevenagel reaction of 5-arylfurfurals1a-fwith 1H-benzimidazol-2-yl) acetonitrile 2a, benzthiazol-2-ylacetonitrile2band (4-arylthiazol-2-yl)-acetonitrile respectively. It was carried out in boiling ethanol in the presence of piperidine as a base. Yields of the reaction products were 81 - 92%.5-Arylfurfurals 1a-fwere obtained by reaction of arendiazonium salts with furfural in Meerwe in reaction conditions³⁸.

The obtained compounds 4-6 orange color, soluble in DMF and DMSO, are practically in soluble in non-polar solvents and water. Their structure is proved with ¹H NMR spectroscopy. In particular, the signals CH = groups - in the form of a singlet at 8.14-8.21ppm and NH in compounds 3a-s at 13.01-13.02 ppm. The 4-H protons signals the thiazole moiety - at 7.12-7.17 ppm.

Pharmacology.

Among all newly synthesized compounds substances 2a-e and 3a-c were selected by the National Cancer Institute (NCI) Developmental Therapeutic Program for the in vitro cell line screening to investigate their anticancer activity.

The human tumor cell lines were derived from nine different cancer types: leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate, and breast cancers. Primary anticancer assays were performed according to the US NCI protocol, which was described elsewhere^39-40.

The results of primary screening are reported as the percent cancer cell line growth (GP%) and are presented in

Table 1.The range of growth % shows the lowest and the highest growth % found among the different cancer cell lines.

Table 1. Cytotoxicity of synthesized compounds at a concentration of 10^-5 Mon 60 lines of cancer cells

Compound	60 cancer cell lines assay in 1-dose 10^{-5 M}
	Mean growth, %	Range of growth, %	The most sensitive cell lines
	Mean growth, %	Range of growth, %	Cell line (Panel)	Growth, %
4a	32.11	3.86 – 65.27	SNB-75 (CNSCancer) ACHN(RenalCancer) 786-0 (RenalCancer) MALME-3M(Melanoma) MDA-MB-231/ATCC(BreastCancer) HOP-92 (NSClung Cancer) UO-31 (RenalCancer) OVCAR-4 (OvarianCancer) CAKI-1 (RenalCancer) OVCAR-3 (OvarianCancer) RXF 393 (RenalCancer) LOXIMVI(Melanoma) HS578T(BreastCancer) A498(RenalCancer) HCT-116 (ColonCancer) UACC-62 (Melanoma) NCI-H460(NSClung Cancer) RPMI-8226 (Leukemia) CCRF-CEM(Leukemia)	29.72 21.98 20.70 18.11 19.27 8.603 5.83 3.86 4.32 5.17 8.09 11.81 12.07 15.95 16.76 19.17 22.44 24.72 38.103
4b	85.47	58.41 – 118.90	SNB-75 (CNS Cancer) ACHN(RenalCancer) HCT-15 (ColonCancer)	58.41 62.35 63.14
4c	98.02	79.04 – 111.92	MDA-MB-468 (BreastCancer)	79.04
5a	102.31	84.49 – 127.16	NCI-H322M(NSClung Cancer)	84.49
5b	98.34	67.66 – 121.49	SK-MEL-5 (Melanoma) EKVX (NSClung Cancer) HOP-62 (NSClung Cancer)	67.66 72.44 80.71
5c	84.86	11.05 – 116.29	HOP-92 (NSClung Cancer) UACC-62 (Melanoma) UO-31 (RenalCancer) SK-MEL-5 (Melanoma)	11.05 41.36 59.15 59.70
6a	97.29	10.12 – 109.15	MDA-MB-468(Breast Cancer) MCF7(Breast Cancer ) T-47D(Breast Cancer )	10.12 25.14 49.56
6b	96.29	18.04–114.33	MDA-MB-468 (Breast Cancer ) MCF7(Breast Cancer ) T-47D(Breast Cancer )	18.04 40.19 55.74
6c	90.32	10.63– 118.82	MDA-MB-468 (Breast Cancer ) T-47D(Breast Cancer ) MCF7(Breast Cancer ) HCC-2998 (Colon Cancer)	28.50 10.63 24.22 49.87

It was established that the obtained of 3-(5-aryl furan-2-yl) acrylonitrile derivatives possess the antitumor activity of different levels (mean GP = 32.11 - 102.31%). Among the 2-benzimidazolyl substituted derivatives, the most active was nitrile with 4-chlorophenyl substituent in the furan nucleus (compound 4a, mean GP = 32.11%). Replacement of chlorine on bromine led to significant loss of activity (4b, mean GP = 85.47%) and 2.5-dichloric substituent to complete loss (4c, mean GP = 98.02%). The compounds with a 2-benzothiazole and 4-aryl substituent also possessed low-activity (mean GP = 84.86-102.31%). But it should be noticed that compounds 6a-c are sensitive to MDA-MB-468 Breast Cancer cell line.

According to the results of the pre-screening, compound 4a was selected for the second phase of the study, consisting in testing on 60 lines of tumor cells in the concentration gradient (100μM, 10μM, 1μM, 0.1μM and 0.01μM). The percentage of growth was evaluated spectrophotometrically versus controls not treated with test agents after 48-h exposure and using SRB protein assay to estimate cell viability or growth. Dose–response parameters were calculated for each cell line: GI₅₀ – molar concentration of the compound that inhibits 50% net cell growth; TGI – molar concentration of the compound leading to the total inhibition; and LC₅₀– molar concentration of the compound leading to 50% net cell death. Furthermore, a mean graph midpoints (MG_MID) were calculated for GI₅₀, giving an average activity parameter over all cell lines for the tested compound. For the MG_MID calculation, insensitive cell lines were included with the highest concentration tested.

The results of in-vitro screening studies (Table 2) indicate a high antitumor activity of compound 4a for all lines of the tested malignant tumor cells. The mean values of GI50 = 7.49μM and TGI = 7.49μM. It was found that the most sensitiveline the: CAKI-1 kidney cancer (GI50 = 1.70μM, TGI = 3.55μM). As for a number of lines of tumor cells, there was a cytotoxic effect. These include, in particular, the SK-MEL-5 and UACC-62 melanoma lines (LC₅₀ = 51.8μM and 73.7μM), OVCAR-3 ovarian cancer (LC₅₀ = 8.33μM), 786-0 and RXF 393 Renal cancer(LC₅₀ = 6.98μM and 7.44μM), MDA-MB-231 / ATCC and MDA-MB-468 breast cancer (LC₅₀ = 25.6μM and 7.53μM).

Table 2. In vitro anticancer activity at 60 human tumor cell lines for compound4a

Disease	Cell line	GI₅₀, µM	TGI, µM	Disease	Cell line	GI₅₀, µM	TGI, µM
Leukemia	CCRF-CEM	>100	>100	Melanoma	LOX IMVI	4.58	32.8
	HL-60(TB)	3.97	>100		MALME-3M	1.88	-
	K-562	21.3	>100		M14	3.28	9.25
	MOLT-4	8.48	>100		MDA-MB-435	3.27	>100
	RPMI-8226	3.99	>100		SK-MEL-2	3.73	43.7
	SR	6.59	>100		SK-MEL-28	2.80	6.89
NSC Lung cancer	A549/ATCC	19.6	>100		SK-MEL-5	2.43	7.48
	EKVX	-	>100		UACC-257	3.35	31.0
	HOP-62	4.41	32.7		UACC-62	3.94	19.9
	HOP-92	2.60	6.64	Ovarian Cancer	IGROV1	4.55	>100
	NCI-H226	9.27	>100		OVCAR-3	2.21	4.29
	NCI-H23	3.83	35.6		OVCAR-4	3.25	10.0
	NCI-H322M	29.6	>100		OVCAR-8	3.96	98.2
	NCI-H460	3.69	14.3		NCI/ADR-RES	2.61	8.21
	NCI-H522	3.23	>100		SK-OV-3	4.57	42.5
Colon Cancer	COLO 205	2.33	-	Renal Cancer	786-0	2.07	3.80
	HCC-2998	8.39	>100		A498	6.35	53.5
	HCT-116	4.20	57.3		ACHN	4.57	>100
	HCT-15	3.49	>100		CAKI-1	1.70	3.55
	HT29	2.34	-		RXF 393	5.82	>100
	KM12	3.08	71.9		SN12C	2.78	5.89
	SW-620	2.26	-		UO-31	2.07	4.12
CNS Cancer	SF-268	4.21	41.5	Breast Cancer	MCF7	2.64	>100
	SF-295	5.94	>100		MDA-MB- 231/ATCC	2.12	25.6
	SF-539	3.48	23.9		MDA-MB- 231/ATCC	2.12	25.6
	SNB-19	24.6	>100		HS 578T	3.54	>100
	SNB-75	2.18	5.48		BT-549	4.52	>100
	U251	3.75	20.1		T-47D	1.56	-
Prostate Cancer	PC-3	15.8	>100		MDA-MB-468	1.55	7.53
Prostate Cancer	DU-145	3.61	76.0

Table 3. Anticancer selectivity pattern of the most active compound 4a fat the GI50 (С, μМ) and TGI (С, μМ) levels

Сpd	Parameters	Subpanel tumor cell lines
Сpd	Parameters	L	NSCLC	ColC	CNSC	M	OV	RC	PC	BC
4а	GI₅₀	24.06	9.529	3.727	7.360	3.251	3.525	3.623	9.705	2.655
	SI*	0.311	0.786	2.010	1.018	2.305	2.126	2.068	0.772	2.822
	TGI	100.0	65.47	82.30	48.50	31.38	43.87	38.69	88.00	66.63
	SI**	0.628	0.959	0.763	1.294	2.000	1.431	1.622	0.713	0.942
Selectivity index at the GI₅₀ (С, μМ) level; Selectivity index at the TGI (С, μМ) level. L – leukemia, NSCLCC – non-small cell lung cancer, ColC – colon cancer, CNSC – CNS cancer, M – melanoma, OV– ovarian cancer, RC – renal cancer, PC – prostate cancer, BC – breast cancer.

Table 4. Mean growth inhibitory concentration (GI50, µM) of compound 4a in comparison with 5-FU, Cisplatin and Curcumin

	Subpanel tumor cell lines
	L	NSCLC	ColC	CNSC	M	OV	RC	PC	BC	MG-MID
4a	24.06	9.529	3.727	7.360	3.251	3.525	3.623	9.705	2.655	7.493
5-FU	15.1	>100	8.4	72.1	70.6	61.4	45.6	22.7	76.4	52.5
Cisplatin	6.3	9.4	21.0	4.7	8.5	6.3	10.2	5.6	13.3	9.48
Curcumin	3.7	9.2	4.7	5.8	7.1	8.9	10.2	11.2	5.9	7.41
Gefitinib	3.54	7.81	7.02	8.14	5.28	6.63	2.67	1.65	7.81	3.24

CONCLUSIONS:

The method of the synthesis of 2-(1H-benzimidazol-2-yl)- and 2-benzothiazol-2-yl-3-(5-arylfuran-2-yl) acrylonitrile was developed. The antitumor activity of the synthesized compounds was investigated. 2-(1H-Benzimidazol-2-yl)-3-[5-(4-chlorophenyl) furan-2-yl]-acrylonitrile as promising for further optimization was identified.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 17.10.2019 Modified on 09.12.2019

Research J. Pharm. and Tech. 2020; 13(8):3690-3696.

DOI: 10.5958/0974-360X.2020.00653.8