Design and Synthesis of Novel 4-Amino-2,3-dihydro-2-imino-3-(1- iminododecyl)thiazole-5-Carbonitrile Derivatives as Antimicrobial Agents

Received: 07-Jun-2020 Accepted Date: Jun 23, 2020 ; Published: 27-Jun-2020

Introduction

1,3-Thiazoles are considered as important heterocyclic compounds and have low toxicity to mammals and have high a broad field in biological activities such as insecticidal [1], antifungal [2-4], herbicidal [5-6], regulating plant growth [7,8], and antiviral activities [9]. A series of thiazole derivatives like thiamethoxam (A) [10], thiabendazole (B), imidaclothiz (C) [11], and benthiavalicarbisopropyl [12] used as agrochemicals. Furthermore, the compounds with an amide or ester group were a versatile class of agrochemicals with a wide range of biological activities (Figure 1) [13,14].

Figure 1: Thiazole derivatives

2-Aminothiazole considered as a skeleton heterocyclic amine, and used as the starting point for synthesis of numerous compounds, containing sulfur drugs, biocides, fungicides, dyes and chemical reaction accelerators and used as intermediates in the preparation of antibiotics, where many of 2-aminothiazoles derivatives have been substituted with different groups for pharmaceutical activities, [15,16] and are also used in the synthesis of many types of dyes for preparation of fibers,[17-19] besides it is used as corrosion activity inhibitors for mild steel protection. Therefore, we synthesized a series of 4-amino-thiazole-5-carbonitrile derivatives.

Experimental Section

General information

The melting points were detected on a Gallenkamp electro thermal melting point apparatus (Weiss-Gallenkamp, Lough borough, UK) and are uncorrected. The ¹HNMR spectra were determined with a Varian Mercury VXR-400 NMR spectrometer (Palo Alto, CA) at plus 400 MHz and used DMSO-d₆ as the solvent. Mass spectra were recorded on a Hewlett Packard MS-5988 spectrometer (Palo Alto, CA) at 70 eV.Microanalyses were confirmed by used Mario El Mentar apparatus. The antimicrobial activity of the synthesized compounds was studies at department of Botany and Microbiology, college of Science, Jouf University,Saudi Arabia.

The general method for preparation of N-phenyldodecanimidoyl chloride derivatives 4a-e

Thionyl chloride (4 ml) was added dropwise to a cold solution of N-phenyldodecanamide derivatives 3a-e (5 mmol) in benzene (10 ml). The reaction mixture stirring at room temperature for 5 h. The solvent was then evaporated and the solid was recrystallized from aqueous ethanol to afford the pure products 4a-e.

The general method for preparation (Z)-N’-phenyl-N-(phenylcarbamothioyl)dodecanimidamide derivatives 6a-e

A solution of dodecanimidoyl chloride derivatives 4a-e (2ml, 0.01 mol) and sodium isothiocyanate (0.01) dissolved in dry acetone (25ml); aniline derivatives (0.01mol) dissolved in dry acetone and added to the solution after stirred at room temperature for 1hr. The solution was refluxed for 4hrs. The solution after cooling was poured into ice-water. The residue was precipitated filtrated and crystallized from petroleum ether (60-80oC) with ethyl acetate to give 6a-e

(Z)-N’-(4-Methoxyphenyl)-N-((4-methoxyphenyl) carbamothioyl) dodecanimidamide (6a).

M.P. 96-98oC.. Yield: 65%. IR (KBr, ν_max cm^-1): 3320 (NH), 3052 (CH-arom), 2927 (aliph-CH), 1359 (C=S), 1605 (C=N). ¹H NMR ( DMSO-d₆, ppm ):δ 11.98 (s,1H, NH), 7.29 (d, 4H, Ar-H), 6.89 (d, 4H, Ar-H), 5.76 (s, 1H, NH), 3.82 (s, 6H, (OCH₃)₂), 2.32 (t,2H, CH₂), 1.59 (m, 2H, CH₂), 1.29 (s, 16H, (CH₂)₈), 0.93 (s, 3H, CH₃). Anal. Calcd. For (C₂₇H₃₉N₃O₂S; 469.69): C, 69.05; H, 8.37; N, 8.95; S, 6.83. Found: C, 69.15; H, 8.35; N, 8.99; S, 6.86

(Z)-N-((4-Methoxyphenyl) carbamothioyl)-N’-(4-nitrophenyl)dodecanimidamide (6b).

M.P. 115-117 oC.Yield: 73%. IR (KBr, νmax cm^-1):3315(NH), 3043 (CH-arom), 2937-2836 (aliph-CH), 1356 (C=S), 1654 (C=N), 1514-1313 (NO2). ¹H NMR ( DMSO-d₆, ppm ):δ 12.29 (s,1H, NH), 7.30 (d, 4H, Ar-H), 6.93 (d, 4H, Ar-H), 5.86 (s, 1H, NH), 3.82 (s, 3H, OCH₃), 2.32 (t,2H, CH₂), 1.59 (m, 2H, CH₂), 1.29 (s, 16H, (CH₂)8), 0.93 (s, 3H, CH₃). Anal. Calcd. For (C₂₆H₃₆N₄O₃S; 484.66): C, 64.43; H, 7.49; N, 11.56; S, 6.61. Found: C, 64.48; H, 7.45; N, 11.59; S, 6.64.

(Z)-N’-(4-Methoxyphenyl)-N-((4-nitrophenyl) carbamothioyl) dodecanimidamide (6c).

M.P. 127-129oC. Yield: 63% IR (KBr, νmax cm^-1):3332 (NH), 2935- 2838 (aliph-CH), 1337 (C=S), 1632 (C=N) 1515-1388 (NO₂).

(Z)-N’-(4-Methoxyphenyl)-N-(phenylcarbamothioyl) dodecanimidamide (6d).

M.P. 162-164 oC. Yield: 83%. IR (KBr, νmax cm^-1):3332 (NH), 2928(aliph-CH), 1347 (C=S), 1639 (C=N).

(Z)-N-((4-Methoxyphenyl)carbamothioyl)-N’-phenyldodecanimidamide (6e)

M.P.196-198oC. Yield: 59%. IR (KBr, νmax cm^-1):3325 (NH), 2927 (aliph-CH), 1313 (C=S), 1636 (C=N). ¹H NMR ( DMSO-d₆, ppm ):δ12.23 (s,1H, NH), 7.34 (d, 4H, Ar-H), 7.02 (m,1H, Ar-H), 6.98 (d, 4H, Ar-H),5.96 (s, 1H, NH), 3.89 (s, 3H, OCH₃), 2.36 (t,2H, CH₂), 1.56 (m, 2H, CH₂), 1.28 (s, 16H, (CH₂)₈), 0.98 (s, 3H, CH₃).MS, m/z (%) (439, 2.49 %, M+). Anal Calcd. For (C₂₆H₃₇N₃OS; 439.66):C, 71.03; H, 8.48; N, 9.56; S, 7.29. Found: C, 71.07; H, 8.51; N, 9.52; S, 7.32

The general procedure of 4-amino-2,3-dihydro-2-(phenylimino)-3-((Z)-1-(phenylimino)dodecyl)thiazole-5- carbonitrile derivatives (8a-e)

A mixture of 6a-e (2.5 mmol) and 7 (1.7 mmol) was dissolved in ethyl acetate and refluxed for 10 hrs, and, then precipitated by adding a mixture of ethyl acetate and diethyl ether to yield compounds 8a-e, crystallization from toluene.

2-(4-Methoxyphenylimino)-3-((Z)-1-(4-methoxyphenylimino) dodecyl)-4-amino-2,3-dihydrothiazole-5-carbonitrile ( 8a)

1HNMR ( DMSO-d₆, ppm ): δ 9.73 (brs, 2H, NH2 exchangable with D2O), 7.36-7.34 (dd, 2H, methoxy-ph, J=9.0), 7.13-7.12 (dd, 2H, methoxy-Ph, J=6.0 ), 7.03 (dd, 2H, methoxy-Ph, J=6.0 ), 7.00 (dd, 2H, methoxy-Ph, J=6.0 3), 3.75 (s, 3H, OCH₃), 3.30 (s, 3H,OCH₃), 2.53 (t, 2H,CH₂), 2.03 (s, 18H, (CH₂)9 ), 1.42 (s, 3H, CH₃). MS,m/z (%) (533.73, 1.49%, M+). Anal. Calcd. For (C₃₀H₃₉N₅O₂S; 533.74): C, 67.51; H, 7.37; N, 13.12; S, 6.01. Found: C, 67.54; H, 7.40; N, 13.16; S, 6.05

3-((Z)-1-(4-Methoxyphenylimino) dodecyl)-2-(4-nitrophenylimino)-4-amino-2,3-dihydrothiazole-5-carbonitrile 8b.

¹H NMR ( DMSO-d₆, ppm ): δ9.98 (s, 2H,NH2 exchangable with D2O), 7.79-7.94 (dd, 2 H, nitro-ph, J=6.0), 7.77 (dd, 2 H, methoxy-Ph, J=6.0 ), 7.56 (dd, 4H,Ar-H), 3.76 (t, 2H,CH₂), 3.32(s, 3H, OCH₃), 2.45(s, 18H, (CH₂)9 ), 1.42 (s, 3H, CH₃). Anal. Calcd. For (C₂₉H₃₆N₆O₃S; 548.71): C, 63.48; H, 6.61; N, 15.32; S, 5.84. Found: C, 63.51 H, 6.58 N, 15.34; S, 5.80.

2-(4-Methoxyphenylimino)-3-((Z)-1-(4-nitrophenylimino) dodecyl)-4-amino-2,3-dihydrothiazole-5-carbonitrile (8c)

¹H NMR ( DMSO-d₆, ppm ):δ9.38(brs, 2H, NH₂ exchangable with D2O ), 7.95-7.92 (dd, 2H, nitro-ph, J=9.0), 7.36 (dd, 2H, methoxy-Ph, J=6.0 ), 7.14(dd, 4H,Ar-H), 3.32(s, 3H, OCH₃), 1.42 (s, 3H, CH₃), 2.45(s, 18H, (CH₂)9 ), 3.07 (t, 2H,CH₂).MS, m/z (%) (548, 1.17 %, M+). Anal. Calcd. For (C₂₉H₃₆N₆O₃S; 548.71): C, 63.48; H, 6.61; N, 15.32; S, 5.84. Found: C, 63.45; H, 6.64; N, 15.36; S, 5.87.

2-(4-Methoxyphenylimino)-4-amino-2,3-dihydro-3-((Z)-1-(phenylimino)dodecyl)thiazole-5-carbonitrile (8d)

¹H NMR ( DMSO-d₆, ppm ): δ 10.18 (brs, 2H, NH2 exchangable with D2O), 7.67 (dd, 2H, methoxy-ph, J=9.0), 7.12 (dd, 2 H, methoxy-Ph, J=6.0 ), 6.98-6.95(m, 5H, Ar-H), 3.77 (t, 2H,CH₂), 2.51 (s, 3H, OCH₃), 2.48 (s, 18H, (CH₂)₉ ), 1.82 (s, 3H, CH₃). MS, m/z (%) (503, 3.19%, M+). Anal. Calcd. For (C₂₉H₃₇N₅OS; 503.7): C, 69.15; H, 7.40; N, 13.90; S, 6.37. Found: 69.18; H, 7.45; N, 13.94; S, 6.40.

3-((Z)-1-(4-Methoxyphenylimino) dodecyl)-4-amino-2,3-dihydro-2-(phenylimino)thiazole-5-carbonitrile 8e

¹H NMR ( DMSO-d₆, ppm ): δ10.18 (brs, 2H, NH2 exchangable with D2O), 7.69 (dd, 2H, methoxy-ph, J=9.0), 7.50-7.42(m, 5H, thiadiazole Ar-H), 7.26 (dd, 2H, methoxy-Ph, J=6.0 ), 3.31 (t, 2H,CH₂), 2.80 (s, 3H, OCH₃), 2.41(s, 18H, (CH₂)₉ ), 1.45 (s,3H,CH₃). Anal. Calcd. For C₂₉H₃₇N₅OS; 503.7): C, 69.15; H, 7.40; N, 13.90; S, 6.37. Found: C, 69.11; H, 7.43; N, 13.93; S, 6.32.

Antimicrobial Activity

The antibacterial activities of 8a-e were tested by the agar well diffusion method [24]. The experiment was repeated 3 times, and the average inhibition zones were measurement. As reported in Table 2, it is obviously observed that the newly synthesized thiazole derivatives have low to moderate effect versus Gram (+ve) (and Bacillus cereus and Staphylococcus aureus) and (Pseudomonas aeruginosa and Escherichia coli) used as Gram (-ve), which compared with Cefotaxime as standard control, while in Table 3, indicate moderate antifungal activity versus (Aspergillus flavus and Aspergillus niger) compared with Clotrimazole drug as control.

Table 2: Antibacterial activities of some synthesized thiazole derivatives (inhibition zones mm)

Table 3: Antifungal activities of some new synthesized thiazole derivatives (inhibition zones mm).

Conclusion

In summary, we report the synthesis and antimicrobial evaluation of some 4-amino-2,3-dihydro-2-imino-3-(1-iminododecyl) thiazole-5-carbonitrile derivatives 8a-e. The prepared compounds showed antimicrobial activity revealing moderate to good activities.

Acknowledgement

A. A.Ghoneim. Thanks Professor Ahmed Fouad El Farargy, Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt for the facilities offered of his effort and abundant facilities in the science of chemistry during the previous stages. The author’s thanks College of Science, Al JoufUniversity, Sakaka, Kingdom of SaudiArabia, Chemistry Department, also much thanks to Faculty of Science, Zagazig University, Zagazig, Egypt and Organometallic and Organometalloid Chemistry Department, National Research Centre, Dokki, Cairo, Egypt for the continuous help and support.

References

[1] C.L. Liu, L& Li and Z.M. L Bioorg. Med. Chem. 2004, 12, 2825.

[2] A.R. Jalilian, S. Sattari, M. Bineshmarvasti et al., Arch. Pharm. Med. Chem. 2000, 333: p. 347.

[3] S. Vengurlekar, S. Prachand, S. Jain et al., Int. J. Pharm. Life Sci. 2014, 53: 526.

[4]A.A. Ghoneim and MG Assy, Org. Chem Curr Res 2015, 4: 3

[5] T.T. Wang, G.F. Bing, X. Zhang et al., Bioorg. Med. Chem. Lett. 2010, 20: p. 3348.

[6] H. Dai, Y.S. Xiao, Z. Li et al., Chin. Chem. Lett. 2014, 25: p. 1014.

[7] X. Qin, H.B. Yu, H. Dai et al., Chin. Chem. Lett. 2010, 21: p. 283.

[8] H.B. Yu, L. Shao and J.X. Fang, J. Organomet. Chem. 2007, 692: p. 991.

[9] A.S. Mayhoub, M. Khaliq, C. Botting et al., Bioorg. Med. Chem. 2011, 19: p. 3845.

[10] P. Maienfisch, M. Angst, F. Brandl et al., Pest Manag. Sci. 2001, 57: p. 906.

[11] M.H. Lee, S.M. Pan, T.W. Ng et al., Int. J. Food Microbiol. 2011, 150: p. 157.

[12] H.C. Feng, World Pestic. 2008, 30: p. 51.

[13] J. Huang, D. Wu, H.J. Ge et al., Chin. Chem. Lett. 2014, 25: p. 1399.

[14] A. Geronikaki, P. Vicini, N. Dabarakis et al., Eur. J. Med. Chem. 2009, 44: p. 473..

[15] R.B. Bakr, A.A. Ghoneim and A.A. Azouz, Bioorganic chemistry 2019, 88: 102964.

[16] C. Papadopoulou, A. Geronikaki and D. Hadjipavlou-Litina, Farmaco 2005, 60: p. 969.

[17] A. Kreutzberger and A. Tantawy, Arch. Pharm. 1981, 314: p. 968.

[18] E. Abdel-Latif, F. A. Amer, M. A. Metwally, M. E. Khalifa, Pigm. Resin.Technol. 2009, 38, 105.

[19] M. E. Khalifa, E. Abdel-Latif, F. A. Amer et al, Int. J. Text. Sci. 2013, 1: p. 62.

[20] A.A. Ghoneim and N.M. Morsy. J. Iran.Chem.Soc. 2018, 15: p. 2567.

[21] A.A .Ghoneim and A.F. El-Farargy, J. Iran. Chem. Soc., 2019, 16: p. 1391.

[22] M. A. Metwally, H. A. Etman, H. E. Gafer et al., Adv. Color Sci. Tech. 2004, 7: p. 71.

[23] M. E. Khalifa, E. Abdel-Latif and A. A. Gobouri, J. Heterocycl. Chem. 2015, 52: p. 674. .

[24] National Committee for Clinical Laboratory Standards (NCCLS) Methods for Dilution Antimicrobial Susceptibility Tests of Bacteria That Grow Aerobically. Approved Standard M100-S12; NCCLS: Wayne. PA, 2002.