INTRODUCTION:

Development of effective antimicrobial and anticancer agents continues to be a great challenge^1-10. The wide variety of biological forms of pathogens, the constant emergence of new multiresistant pathogenic strains make it difficult to treat and prevent infectious diseases. On the other hand cancer is also a very dangerous disease. Not with standing, the progress observed in cancer treatments in the past decades, epidemiology data, clearly point to urgent new therapeutic approaches to control the disease. In order to overcome these restrictions worldwide, the development of new effective and safe anti-antimicrobial and anticancer drugs is continuing.

The furane derivatives play important role in medical and pharmaceutical chemistry^11-21. They exhibit a wide range of biological activity such as antitubercular²², antitumor^23,²⁴, antimalarial²⁵, antibacterial²⁶, antiviral²⁶, and other.

They are inhibitors of aldose reductase²⁷, farnesyltransferase²⁸, HCVNS5B polymerase²⁹and protein tyrosine phosphatase³⁰. Arylfurane derivatives are ligands of Retinoid X³¹, nicotinic acid HCA2³², sphingosine-1-phosphate 4(S1P4)³³, metabotropic glutamate 4 (mGlu4)³⁴, and other receptors. Several compounds with arylfurane moiety are used as medicaments³⁵.

In our previous works we developed a lot of methods of design of combinatorial libraries of five- and six-membered oxygen^36-38 and nitrogen^39-54 containing heterocycles based on diazonium salts. The advantage of the proposed method is that the synthesis of are nediazonium salt is very simple from aromatic amines that are abundantly available in the commercial market with low price. It means that variety of different substituents in organic molecules can be introduction. It very importantly for purposes of medical chemistry. In this article we described synthesis of arylamides of 5-arylfuran-2-carboxylic acids using as started material diazonium salts and evolution of antimicrobial and anticancer activities of prepared compounds.

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).

General procedure of preparation N-(R¹-phenyl)-5-(R-phenyl)-2-furamides (6a-k). A solution of 0.005 mol 5-aryl-2-furoyl chloride 0.005 mol arylamine and 0.6 ml triethylamine in 20mL dioxane, were stirred at room temperature for 1 hours. Next the mixture was poured in 50ml of water. The resulting solid was filtered, washed with water, dried, and crystallized with ethanol-DMFA.

N-(2-chlorophenyl)-5-(4-fluorophenyl)-2-furamide (6a). Yield 84%; mp = 145–146^○C. ¹H NMR: δ_H= 9.65 (s, 1H, NH), 7.97–7.93 (m, 2H, Ar), 7.81 (d, J 7.8 Hz, 1H, Ar), 7.50 (d, J 7.9 Hz, 1H, Ar), 7.42–7.18 (m, 5H, Ar+Fu), 7.02 (d, J 3.7 Hz, 1H, Fu). Anal. Calculated for C₁₇H₁₁ClFNO₂: C, 64.67; H, 3.51; N, 4.44. Found: C, 64.87; H, 3.42; N, 4.55.

5-(4-Fluorophenyl)-N-(2-methoxyphenyl)-2-furamide (6b). Yield 84%; mp 118–120^○C. ¹H NMR: δ_H= 9.09 (s, 1H. NH), 8.01 (d, J 8.0 Hz, 1H, Ar), 7.94–7.87 (m, 2H, Ar), 7.30–7.21 (m, 2H, Ar+Fu), 7.15–6.91 (m, 4H, Ar+Fu), 3.94 (s, 3H, CH₃). Anal. Calculated for C₁₈H₁₄FNO₃: C, 69.45; H, 4.53; N, 4.50. Found: C, 69.57; H, 4.62; N, 4.65.

N-(2,5-dimethylphenyl)-5-(4-fluorophenyl)-2-furamide (6c). Yield 88%; mp 114–115^○C.¹H NMR: δ_H= 9.66 (s, 1H, NH), 7.98 (dd, J 8.9, 5.4 Hz, 2H, Ar), 7.24–7.16 (m, 4H, Ar+Fu), 7.12 (d, J 7.8 Hz, 1H, Ar), 6.97 (d, J 3.6 Hz, 1H, Fu), 6.95 (s, 1H, Ar), 2.33 (s, 3H, CH₃), 2.23 (s, 3H, CH₃). Anal. Calculated for C₁₉H₁₆FNO₂: C, 73.77; H, 5.21; N, 4.53. Found: C, 73.90; H, 5.09; N, 4.41.

N-phenyl-5-[2-(trifluoromethyl)phenyl]-2-furamide (6d). Yield 85%; mp 112-113^○C. ¹H NMR: δ_H= 9.95 (s, 1H, NH), 8.06 (d, J 7.8 Hz, 1H, Ar), 7.85–7.72 (m, 4H, Ar), 7.62 (t, J 7.7 Hz, 1H, Ar), 7.42–7.37 (m, 1H, Fu), 7.31 (t, J 8.0 Hz, 2H, Ar), 7.07 (dd, J 10.5 Hz, 4.2 Hz, 2H, Ar), 6.88 (d, J 3.6 Hz, 1H, Fu). Anal. Calculated for C₁₈H₁₂F₃NO₂: C, 65.26; H, 3.65; N, 4.23. Found: C, 65.39; H, 3.70; N, 4.11.

N-(2-methylphenyl)-5-[2-(trifluoromethyl)phenyl]-2-furamide (6e). Yield 75%; mp 72-73^○C. ¹H NMR: δ_H= 9.44 (s, 1H, NH), 8.06 (d, J 7.8 Hz, 1H, Ar), 7.84 (d, J 8.1 Hz, 1H, Ar), 7.76 (t, J 7.8 Hz, 1H, Ar), 7.61 (s, 1H, Ar), 7.49 (d, J 7.7 Hz, 1H, Ar), 7.33 (d, J 3.6 Hz, 1H, Fu), 7.27–7.09 (m, 3H, Ar), 6.91 (d, J 3.7 Hz, 1H, Fu), 2.29 (s, 3H, CH₃). Anal. Calculated for C₁₉H₁₄F₃NO₂: C, 66.09; H, 4.09; N, 4.06. Found: C, 66.21; H, 4.00; N, 4.23.

N-(2-fluorophenyl)-5-[2-(trifluoromethyl)phenyl]-2-furamide (6f). Yield 71%; mp 86–87^○C. ¹H NMR: δ_H= 9.52 (s, 1H, NH), 8.03 (d, J 7.9 Hz, 1H, Ar), 7.86 (t, J 8.5 Hz, 2H, Ar), 7.77 (t, J 7.7 Hz, 1H, Ar), 7.63 (t, J 7.5 Hz, 1H, Ar), 7.41 (d, J 3.2 Hz, 1H, Fu), 7.23–7.18 (m, 3H, Ar), 6.93 (d, J 3.6 Hz, 1H, Fu). Anal. Calculated for C₁₈H₁₁F₄NO₂: C, 61.90; H, 3.17; N, 4.01. Found: C, 62.07; H, 3.08; N, 4.15.

N-(2-chlorophenyl)-5-[2-(trifluoromethyl)phenyl]-2-furamide (6g). Yield 83%; mp 93–94^○C. ¹H NMR: δ_H= 9.26 (s, 1H, NH), 8.08 (d, J 8.1 Hz, 1H, Ar), 7.98 (d, J 8.0 Hz, 1H, Ar), 7.86 (d, J 7.9 Hz, 1H, Ar), 7.77 (t, J 7.8 Hz, 1H, Ar), 7.65 (d, J 7.7 Hz, 1H, Ar), 7.48 (dd, J 8.0 Hz, 1.4 Hz, 1H, Ar), 7.43–7.32 (m, 2H, Ar+Fu), 7.23–7.17 (m, 1H, Ar), 6.97 (d, J 3.5 Hz, 1H, Fu). Anal. Calculated for C₁₈H₁₁ClF₃NO₂: C, 59.11; H, 3.03; N, 3.83. Found: C, 59.30; H, 2.95; N, 3.89.

5-(2,6-Dichlorophenyl)-N-(4-methoxyphenyl)-2-furamide (6h). Yield 78%; mp 128–130^○C. ¹H NMR: δ_H= 9.87 (s, 1H, NH), 7.63 (d, J 9.0 Hz, 2H, Ar), 7.58–7.47 (m, 3H, Ar), 7.37 (d, J 3.5 Hz, 1H, Fu), 6.84 (d, J 9.0 Hz, 2H, Ar), 6.70 (d, J 3.5 Hz, 1H, Fu), 3.76 (s, 3H, CH₃). Anal. Calculated for C₁₈H₁₃Cl₂NO₃: C, 59.69; H, 3.62; N, 3.87. Found: C, 59.81; H, 3.49; N, 3.99.

N-(2-chlorophenyl)-5-(4-methyl-2-nitrophenyl)-2-furamide (6i). Yield 91%; mp 213–214^○C. ¹H NMR: δ_H= 10.83 (s, 1H, NH), 8.07 (d, J 9.1 Hz, 1H, Ar), 7.99 (s, 1H, Ar), 7.85 (d, J 8.0 Hz, 1H, Ar), 7.59 (d, J 3.6 Hz, 1H, Fu), 7.49 (t, J 7.9 Hz, 1H, Ar), 7.40–7.30 (m, 3H, Ar), 7.20 (d, J 3.6 Hz, 1H, Fu), 3.82 (s, 3H, CH₃). Anal. Calculated for C₁₈H₁₃ClN₂O₄: C, 60.60; H, 3.67; N, 7.85. Found: C, 60.78; H, 3.49; N, 7.98.

N-(4-acetylphenyl)-5-(4-chloro-2-nitrophenyl)-2-furamide (6j). Yield 87%; mp 223–224^○C. ¹H NMR: δ_H= 10.31 (s, 1H, NH), 8.12 (d, J 8.5 Hz, 1H, Ar), 8.04 (d, J 2.1 Hz, 1H, Ar), 7.96–7.82 (m, 5H, Ar), 7.47 (d, J 3.7 Hz, 1H, Fu), 6.87 (d, J 3.7 Hz, 1H, Fu), 2.54 (s, 3H). Anal. Calculated for C₁₉H₁₃ClN₂O₅: C, 59.31; H, 3.41; N, 7.28. Found: C, 59.43; H, 3.25; N, 7.34.

5-(4-Chloro-2-nitrophenyl)-N-(2-chlorophenyl)-2-furamide (6k). Yield 76%; mp 145–146^○C.¹H NMR: δ_H= 9.37 (s, 1H, NH), 8.10 (d, J 8.5 Hz, 1H, Ar), 8.03 (s, 1H, Ar), 7.94 (d, J 8.1 Hz, 1H, Ar), 7.81 (d, J 8.5 Hz, 1H, Ar), 7.49 (d, J 8.0 Hz, 1H, Ar), 7.40 (d, J 3.7 Hz, 1H, Fu), 7.35 (t, J 7.8 Hz, 1H, Ar), 7.21 (t, J 7.8 Hz, 1H, Ar), 7.01 (d, J 3.6 Hz, 1H, Fu).Anal. Calculated for C₁₇H₁₀Cl₂N₂O₄: C, 54.13; H, 2.67; N, 7.43. Found: C, 54.24; H, 2.53; N, 7.56.

Biology (microbiology):

Antibacterial data collection to signify bacterial strains and growth conditions:

Inhibition of bacterial growth was determined measuring absorbance at 600 nm (OD600), using a Tecan M1000 Pro monochromator plate reader. The percentage of growth inhibition was calculated for each of them, using the negative control (media only) and positive control (bacteria without inhibitors) at the same time as references.

Antifungal data collection:

Growth inhibition of C. albicans was determined measuring absorbance at 530nm (OD530), while the growth inhibition of C. neoformans was determined measuring the difference in absorbance between 600 and 570nm (OD600-570), after the addition of resazurin (0.001% final concentration) and incubation at 35°C for additional 2 h. The absorbance was measured using a Biotek Synergy HTX plate reader. The percentage of growth inhibition was calculated for each of them, using the negative control (media only) and positive control (bacteria without inhibitors) at the same time as references.

Inhibition:

Percentage growth inhibition of an individual sample is based on Negative controls (media only) and positive controls (bacterial/fungal media without inhibitors). Negative inhibition values indicate that the growth rate (or OD600) is higher compared to the Negative Control (Bacteria/fungi only, set to 0% inhibition). The growth rates for all bacteria and fungi has a variation of -/+ 10%, which is within the reported normal distribution of bacterial/fungal growth (https://www.co-add.org).

Biology (anticancer activity against malignant human tumor cells):

A primary anticancer assay was performed on a panel of approximately 60 human tumor cell lines derived from nine neoplastic diseases, in accordance with the protocol of the Drug Evaluation Branch, National Cancer Institute, Bethesda. The tested compounds were added to the culture at a single concentration (10⁻⁵M) and the cultures were incubated for 48 h. Endpoint determinations were made with a protein binding dye, sulforhodamine B (SRB). Results for each tested compound were reported as the percent growth of the treated cells when compared to the untreated control cells. The percent growth was evaluated spectrophotometrically versus controls not treated with the test agents. The cytotoxic and/or growth inhibitory effects of the most active selected compounds were tested in vitro against the full panel of about 60 human tumor cell lines at 10-fold dilutions of five concentrations ranging from 10⁻⁴to 10⁻⁸M. The 48-h continuous drug exposure protocol was followed and an SRB protein assay was used to estimate cell viability or growth.

Using the seven absorbance measurements [time zero, (Tz), control growth in the absence of drug, (C), and test growth in the presence of drug at the five concentration levels (Ti)], the percent growth was calculated at each of the drug concentrations levels. Percent growth inhibition was calculated as:

Ti − Tz

–––––––× 100 for concentrations for which Ti ≥ Tz

C – Tz

Ti − Tz

––––––– × 100 for concentrations for which Ti <Tz.

Three dose-response parameters were calculated for each compound. Growth inhibition of 50% (GI₅₀) was calculated from [(Ti − Tz)/(C − Tz)] × 100 − 50, which is the drug concentration resulting in a 50% lower net protein increase in the treated cells (measured by SRB staining) as compared to the net protein increase seen in the control cells. The drug concentration resulting in total growth inhibition (TGI) was calculated from Ti = Tz. The LC₅₀ (concentration of drug resulting in a 50% reduction in the measured protein at the end of the drug treatment as compared to that at the beginning) indicating a net loss of cells following treatment was calculated from [(Ti − Tz)/Tz] × 100 = -50. Values were calculated for each of these three parameters if the level of activity was reached; however, if the effect was not reached or was exceeded, the value for that parameter was expressed as more or less than the maximum or minimum concentration was tested.

RESULTS AND DISCUSSION:

Chemistry:

Continuing systematic study of various derivatives of furan as potential drug candidates we represented synthesis and antimicrobial and anticancer properties evaluation of some N-(R¹-phenyl)-5-(R-phenyl)-2-furamides. Our synthesis started from aromatic diazonium salts 1a-e and furan-2-carboxylic acids 2. At first stage compound 2 under goes arylation in Meerwein reaction conditionaccording methods described in literature⁵⁵. As a result 5-arylfuran-2-carboxylic acids 3a-e were synthesized. To prepare target furamides 6a-k the acids 3a-e were transformed into appropriated acylchlorides 4a-e. They were used in acylation of arylamines 5a-h. The reaction was performed in dioxane at room temperature.

Table 1. Antimicrobial activity compounds 6a-k.

Compound	*S. aureus* *ATCC* *43300*	*E. coli* *ATCC* *25922*	*K. pneumoniae* *ATCC 700603*	P. aeruginosa *ATCC 27853*	A. baumannii *ATCC 19606*	*C.albicans* *ATCC* *90028*	C. neoformans *ATCC 208821*
6a	20.3; 14.9	1.2; 1.4	2.8; 29.0	-9.9; -8.1	11.1; 12.2	14.3; 16.1	34.1; 38.7
6b	13.1; 34.9	2.8; 5.8	-0.5;5.3	2.1; 3.3	2.8; 4.7	9.5; 8.4	46.3; 41.4
6c	11.2; 22.5	8.1; 4.9	-3.8; 8.1	0.9; 3.3	4.8; 5.5	4.4; 5.7	44.7; 54.1
6d	11.4; -7.3	7.2; 8.0	40.1; 52.3	3.9; 4.2	13.2; 14.6	13.2; 8.4	91.9; 89.8
6e	11.5; 12.3	-3.5; 1.2	51.4; 59.3	14.2; 8.0	-2.5; -7.4	10.2; 9.8	90.5; 88.5
6f	10.2; 21.4	5.9; 2.7	38.6; 46.5	-0.5; 4.7	-21.3; 0.6	11.4; 16.5	96.9; 98.2
6g	23.5; 18.4	5.1; 2.3	31.3; 36.8	2.8; 2.5	0.9; 0.7	14.3; 18.0	62.0; 69.8
6h	21.6; 7.8	4.2; 5.4	2.8; 7.0	5.4; -0.1	8.5; 15.4	8.0; 10.9	15.8; 17.4
6i	2.5; 3.7	4.9; 6.4	31.6; 35.5	3.4; -4.4	11.0; 12.5	-1.6; 2.5	21.9; 25.5
6j	12.4; 18.5	2.4; 4.5	41.7 ;44.3	11.1; 6.8	15.3; 16.8	11.5; 12.4	22.2; 29.4
6k	15.6; 15.4	6.2; -0.3	37.9; 39.8	9.7; 13.5	-0.5; -1.8	0.2; 6.5	23.4; 32.7

Biology (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^57-60. The results for each compound are reported as the percent growth (GP) (table 3). Range of growth (%) shows the lowest and the highest growth that was found among different cancer cell lines.

The synthesized compounds displayed moderate activity in vitro screening on the tested cell lines. However, there was a selective in fluence observed in some of the compounds on several cancer cell lines (table3). Compound 6i have been found to be high active against PC-3 Prostate Cancer (GP = 34.42%), HT29 Colon Cancer (GP = 52.60%), RPMI-8226 (GP = 50.71%), HL-60(TB) (GP = 53.79%), K-562 (GP = 57.83%), CCRF-CEM (GP = 59.09%) Leukemia cell lines; 6e – UO-31 Renal Cancer cell line (GP = 59.06%) and 6f – SR Leukemia cell line (GP = 59.81%). The influence of substitutes in aryl fragments of tested compounds were not observed.

CONCLUSIONS:

In our present work, we presented an efficient synthesis, antimicrobial activity and anticancer activities evaluation of some N-(R¹-phenyl)-5-(R-phenyl)-2-furamides. We have shown that the proposed approaches provide the possibility to design furamides diversity with a considerable chemical novelty. The compounds 6d-f with high antimicrobial activity against C. Neoformans ATCC 208821 were identified. Within the framework of the International Research Program DTP (Developmental Therapeutic Program) of the National Cancer Institute's (NCI, Betezda, Merilend, USA) antitumor activity screening of synthesized compounds was carried out. It has been estimated that researched compounds possess moderate antitumor action. However, there was a selective influence observed in some of the compounds on several cancer cell lines. Further optimization of the structure to improve their activities is currently in progress.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 03.03.2020 Modified on 09.05.2020

Research J. Pharm. and Tech. 2020; 13(12):5837-5843.

DOI: 10.5958/0974-360X.2020.01017.3

Compound	MIC	HkСС₅₀	Hm HC₁₀	SI = HC₁₀/ MIC
6d	16; 16	>32; >32	>32; >32	>2; >2
6e	8; 8	>32; >32	>32; >32	>4; >4
6f	16; 16	>32; >32	>32; >32	>2; >2

Test compounds	Average growth, %	Range of growth, %	Most sensitive cell line (cancer line/type) GP, %
6a	106.41	88.99 - 137.33	UO-31 (Renal Cancer) 88.99
6b	109.38	81.15 - 127.57	UO-31 31 (Renal Cancer) 81.15
6c	97.55	66.39 - 141.88	HOP-92 (Non-Small Cell Lung Cancer)66.39 HL-60(TB) (Leukemia) 71.64 MOLT-4 (Leukemia) 81.29
6e	98.36	59.06 - 113.88	UO-31 (Renal Cancer) 59.06 IGROV1 (Ovarian Cancer) 76.43
6f	89.73	59.81 - 118.40	SR (Leukemia) 59.81 MALME-3M (Melanoma) 64.18 UO-31 (Renal Cancer) 67.32
6h	95.69	70.81 - 118.45	UO-31 (Renal Cancer) 70.81 HL-60(TB) (Leukemia) 73.24 SR (Leukemia) 76.58
6i	84.07	34.42 - 122.56	PC-3 (Prostate Cancer) 34.42 RPMI-8226 (Leukemia) 50.71 HT29(Colon Cancer) 52.60 HL-60(TB) (Leukemia) 53.79 K-562 (Leukemia) 57.83 CCRF-CEM (Leukemia) 59.09 MOLT-4 (Leukemia) 71.41
6j	106.77	81.97 - 128.20	UO-31 (Renal Cancer) 81.97
6k	97.55	66.39 - 141.88	HOP-92 (Non-Small Cell Lung Cancer) 66.39 HL-60(TB) (Leukemia)71.64