Synthesis and Evaluation of Novel Fluorobenzimidazole Derivatives as Antibacterial and Antifungal Agents

D. Joshi; R. Narigara; G. Jani; K. Parikh

doi:10.14233/ajomc.2019.AJOMC-P200

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Abstract

A new class of fluorobenzimidazole derivatives (III_a-j)was synthesized to investigate their antimicrobial potential. All the compounds were prepared by multiple step synthesis, initiating from the synthesis of 5-(difluoromethoxy)-1H-benzimidazole-2-thiol (I). The compound I was further reacted with different derivatives of 2-chloro-N-phenylacetamide (II_a-j) prepared by reacting differently substituted anilines with chloroacetylchloride and triethylamine in DMF (solvent); resulting in formation of fluorobenzimidazoles III_a-j. The compounds III_a-j were characterized by spectral analysis viz. ¹H NMR, ¹³C NMR, mass spectra, elemental analysis and IR. All these compounds were screened in vitro for their antimicrobial activity against Gram-positive (S. aureus and E. faecalis) and Gram-negative bacterial (E. coli and P.aeruginosa) strains as well as fungi (A. niger and C. albicans). Some of the compounds exhibited promising results (in MIC) against Gram-negative bacterial strains.

Keywords

Benzimidazole Fluorine Antimicrobial activity

How to Cite

Joshi, D., Narigara, R., Jani, G., & Parikh, K. (2019). Synthesis and Evaluation of Novel Fluorobenzimidazole Derivatives as Antibacterial and Antifungal Agents. Asian Journal of Organic & Medicinal Chemistry, 4(4), 209–215. https://doi.org/10.14233/ajomc.2019.AJOMC-P200

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References

D. Joshi and K. Parikh, Synthesis and Evaluation of Novel Benzimi-dazole Derivatives as Antimicrobial Agents, Med. Chem. Res., 23, 1290 (2014); https://doi.org/10.1007/s00044-013-0732-z.
H.M. Refaat, Synthesis and Anticancer Activity of Some Novel 2-Substi-tuted Benzimidazole Derivatives, Eur. J. Med. Chem., 45, 2949 (2010); https://doi.org/10.1016/j.ejmech.2010.03.022.
M. Shaharyar, M.M. Abdullah, M.A. Bakht and J. Majeed, Pyrazoline Bearing Benzimidazoles: Search for Anticancer Agent, Eur. J. Med. Chem., 45, 114 (2010); https://doi.org/10.1016/j.ejmech.2009.09.032.
A. El-masry, H.H. Fahmy and S.H.A. Abdelwahed, Molecules, 5, 1429 (2000); https://doi.org/10.3390/51201429.
H. Göker, S. Özden, S. Yildiz and D. Boykin, Synthesis and Potent Antibacterial Activity against MRSA of Some Novel 1,2-disubstituted-1H-benzimidazole-N-alkylated-5-carboxamidines, Eur. J. Med. Chem., 40, 1062 (2005); https://doi.org/10.1016/j.ejmech.2005.05.002.
K.G. Sekar and S.K. Periyasamy, Oxidation of Thioacids by Quinaldi-nium Fluorochromate, Arab. J. Chem., 9, 574 (2016); https://doi.org/10.1016/j.arabjc.2013.11.022.
G. Navarrete-Vázquez, R. Cedillo, A. Hernández-Campos, L. Yépez, F. Hernández-Luis, J. Valdez, R. Morales, R. Cortés, M. Hernández and R. Castillo, Synthesis and Antiparasitic Activity of 2-(Trifluoromethyl)-benzimidazole Derivatives, Bioorg. Med. Chem. Lett., 11, 187 (2001); https://doi.org/10.1016/S0960-894X(00)00619-3.
K.M. Hosamani, K.C. Achar and H.R. Seetharamareddy, in vivo Anal-gesic and Anti-inflammatory Activities of Newly Synthesized Benzimidazole Derivatives, Eur. J. Med. Chem., 45, 2048 (2010); https://doi.org/10.1016/j.ejmech.2010.01.029.
K. Parikh and D. Joshi, Antibacterial and Antifungal Screening of Newly Synthesized Benzimidazole-Clubbed Chalcone Derivatives, Med. Chem. Res., 22, 3688 (2013); https://doi.org/10.1007/s00044-012-0369-3.
Z.M. Nofal, H.H. Fahmy and H.S. Mohamed, Synthesis, Antimicrobial and Molluscicidal Activities of New Benzimidazole Derivatives, Arch. Pharm. Res., 25, 28 (2002); https://doi.org/10.1007/BF02975257.
T. Middleton, H.B. Lim, D. Montgomery, T. Rockway, H. Tang, X. Cheng, L. Lu, H. Mo, W.E. Kohlbrenner, A. Molla and W.M. Katti, Inhibition of Human Immunodeficiency Virus Type I Integrase by Naphthamidines and 2-aminobenzimidazoles, Antiviral Res., 64, 35 (2004); https://doi.org/10.1016/j.antiviral.2004.04.007.
A.T. Mavrova, K.K. Anichina, D.I. Vuchev, J.A. Tsenov, P.S. Denkova, M.S. Kondeva and M.K. Micheva, Antihelminthic activity of Some Newly Synthesized 5(6)-(un)Substituted-1H-benzimidazol-2-ylthio-acetylpiperazine Derivatives, Eur. J. Med. Chem., 41, 1412 (2006); https://doi.org/10.1016/j.ejmech.2006.07.005.
V. Klimesová, J. Koèí, K. Waisser and J. Kaustová, New Benzimidazole Derivatives as Antimycobacterial Agents, Il Farmaco, 57, 259 (2002); https://doi.org/10.1016/S0014-827X(02)01218-1.
H. Minoura, S. Takeshita, M. Ita, J. Hirosumi, M. Mabuchi, I. Kawamura, S. Nakajima, O. Nakayama, H. Kayakiri, T. Oku, A. Ohkubo-Suzuki, M. Fukagawa, H. Kojo, K. Hanioka, N. Yamasaki, T. Imoto, Y. Kobayashi and S. Mutoh, Pharmacological Characteristics of a Novel Nonthiazolidinedione Insulin Sensitizer, FK614, Eur. J. Pharmacol., 494, 273 (2004); https://doi.org/10.1016/j.ejphar.2004.04.038.
G. Ayhan-Kilcigil, C. Kus, T. Çoban, B. Can-Eke and M. Iscan, Synth-esis and Antioxidant Properties of Novel Benzimidazole Derivatives, J. Enzyme Inhib. Med. Chem., 19, 129 (2004); https://doi.org/10.1080/1475636042000202017.
H. Nakano, T. Inoue, N. Kawasaki, H. Miyataka, H. Matsumoto, T. Taguchi, N. Inagaki, H. Nagai and T. Satoh, Synthesis and Biological Activities of Novel Antiallergic Agents with 5-lipoxygenase Inhibiting Action, Bioorg. Med. Chem., 8, 373 (2000); https://doi.org/10.1016/S0968-0896(99)00291-6.
S. Dixit, P. Sharma and N. Kaushik, Synthesis of Novel Benzimidazole Derivatives: As Potent Analgesic Agent, Med. Chem. Res., 22, 900 (2013); https://doi.org/10.1007/s00044-012-0083-1.
G. Mariappan, R. Hazarika, F. Alam, R. Karki, U. Patangia and S. Nath, Synthesis and Biological Evaluation of 2-Substituted Benzimidazole Derivatives, Arab. J. Chem., 8, 715 (2015); https://doi.org/10.1016/j.arabjc.2011.11.008.
S. Estrada-Soto, R. Villalobos-Molina, F. Aguirre-Crespo, J. Vergara-Galicia, H. Moreno-Diaz, M. Torres-Piedra and G. Navarrete-Vazquez, Relaxant Activity of 2-(Substituted phenyl)-1H-benzimidazoles on Isolated Rat aortic Rings: Design and Synthesis of 5-Nitro Derivatives, Life Sci., 79, 430 (2006); https://doi.org/10.1016/j.lfs.2006.01.019.
S.M. Badr, H.M. Eisa, A.M. Barghash and A.A. Farahat, Synthesis & Antimicrobial Activity of Certain Benzimidazole and Fused Benzimi-dazole Derivatives, Indian J. Chem., 49B, 1515 (2011).
Y. Radha, A. Manjula, B.M. Reddy and B.V. Rao, Synthesis and Biological Activity of Novel Benzimidazoles, Indian J. Chem., 50B, 1762 (2011).
M.A. Pagano, F. Meggio, M. Ruzzene, M. Andrzejewska, Z. Kazimierczuk and L.A. Pinna, 2-Dimethylamino-4,5,6,7-tetrabromo-1H-benzimi-dazole: A Novel Powerful and Selective Inhibitor of Protein Kinase CK2, Biochem. Biophys. Res. Commun., 321, 1040 (2004); https://doi.org/10.1016/j.bbrc.2004.07.067.
C. McBride, P. Renhowe, C. Heise, J. Jansen, G. Lapointe, S. Ma, R. Pineda, J. Vora, M. Wiesmann and C. Shafer, Design and Structure-Activity Relationship of 3-Benzimidazol-2-yl-1H-indazoles as Inhibitors of Receptor Tyrosine Kinases, Bioorg. Med. Chem. Lett., 16, 3595 (2006); https://doi.org/10.1016/j.bmcl.2006.03.069.
K. Starcevic, M. Kralj, K. Ester, I. Sabol, M. Grce, K. Pavelic and G. Karminski-Zamola, Synthesis, Antiviral and Antitumor Activity of 2-Substituted-5-amidino-benzimidazoles, Bioorg. Med. Chem., 15, 4419 (2007); https://doi.org/10.1016/j.bmc.2007.04.032.
Salahuddin, M. Shaharyar, A. Mazumder and M.M. Abdullah, Synthesis, Characterization and Antimicrobial Activity of 1,3,4-Oxadiazole bearing 1H-Benzimidazole Derivatives, Arab. J. Chem., 10, 503 (2017); https://doi.org/10.1016/j.arabjc.2012.10.010.
H. Kadri, C.S. Matthews, T.D. Bradshaw, M.F.G. Stevens and A.D. Westwell, Synthesis and Antitumour Evaluation of Novel 2-Phenyl-benzimidazoles, J. Enzyme Inhib. Med. Chem., 23, 641 (2008); https://doi.org/10.1080/14756360802205398.
M.-L. Wang and B.-L. Liu, Synthesis of 2-mercaptobenzimidazole from the Reaction of o-Phenylene Diamine and Carbon Disulfide in the Presence of Potassium Hydroxide, J. Chin. Inst. Chem. Eng., 38, 161 (2007); https://doi.org/10.1016/j.jcice.2007.01.003.

References

D. Joshi and K. Parikh, Synthesis and Evaluation of Novel Benzimi-dazole Derivatives as Antimicrobial Agents, Med. Chem. Res., 23, 1290 (2014); https://doi.org/10.1007/s00044-013-0732-z.

H.M. Refaat, Synthesis and Anticancer Activity of Some Novel 2-Substi-tuted Benzimidazole Derivatives, Eur. J. Med. Chem., 45, 2949 (2010); https://doi.org/10.1016/j.ejmech.2010.03.022.

M. Shaharyar, M.M. Abdullah, M.A. Bakht and J. Majeed, Pyrazoline Bearing Benzimidazoles: Search for Anticancer Agent, Eur. J. Med. Chem., 45, 114 (2010); https://doi.org/10.1016/j.ejmech.2009.09.032.

A. El-masry, H.H. Fahmy and S.H.A. Abdelwahed, Molecules, 5, 1429 (2000); https://doi.org/10.3390/51201429.

H. Göker, S. Özden, S. Yildiz and D. Boykin, Synthesis and Potent Antibacterial Activity against MRSA of Some Novel 1,2-disubstituted-1H-benzimidazole-N-alkylated-5-carboxamidines, Eur. J. Med. Chem., 40, 1062 (2005); https://doi.org/10.1016/j.ejmech.2005.05.002.

K.G. Sekar and S.K. Periyasamy, Oxidation of Thioacids by Quinaldi-nium Fluorochromate, Arab. J. Chem., 9, 574 (2016); https://doi.org/10.1016/j.arabjc.2013.11.022.

G. Navarrete-Vázquez, R. Cedillo, A. Hernández-Campos, L. Yépez, F. Hernández-Luis, J. Valdez, R. Morales, R. Cortés, M. Hernández and R. Castillo, Synthesis and Antiparasitic Activity of 2-(Trifluoromethyl)-benzimidazole Derivatives, Bioorg. Med. Chem. Lett., 11, 187 (2001); https://doi.org/10.1016/S0960-894X(00)00619-3.

K.M. Hosamani, K.C. Achar and H.R. Seetharamareddy, in vivo Anal-gesic and Anti-inflammatory Activities of Newly Synthesized Benzimidazole Derivatives, Eur. J. Med. Chem., 45, 2048 (2010); https://doi.org/10.1016/j.ejmech.2010.01.029.

K. Parikh and D. Joshi, Antibacterial and Antifungal Screening of Newly Synthesized Benzimidazole-Clubbed Chalcone Derivatives, Med. Chem. Res., 22, 3688 (2013); https://doi.org/10.1007/s00044-012-0369-3.

Z.M. Nofal, H.H. Fahmy and H.S. Mohamed, Synthesis, Antimicrobial and Molluscicidal Activities of New Benzimidazole Derivatives, Arch. Pharm. Res., 25, 28 (2002); https://doi.org/10.1007/BF02975257.

T. Middleton, H.B. Lim, D. Montgomery, T. Rockway, H. Tang, X. Cheng, L. Lu, H. Mo, W.E. Kohlbrenner, A. Molla and W.M. Katti, Inhibition of Human Immunodeficiency Virus Type I Integrase by Naphthamidines and 2-aminobenzimidazoles, Antiviral Res., 64, 35 (2004); https://doi.org/10.1016/j.antiviral.2004.04.007.

A.T. Mavrova, K.K. Anichina, D.I. Vuchev, J.A. Tsenov, P.S. Denkova, M.S. Kondeva and M.K. Micheva, Antihelminthic activity of Some Newly Synthesized 5(6)-(un)Substituted-1H-benzimidazol-2-ylthio-acetylpiperazine Derivatives, Eur. J. Med. Chem., 41, 1412 (2006); https://doi.org/10.1016/j.ejmech.2006.07.005.

V. Klimesová, J. Koèí, K. Waisser and J. Kaustová, New Benzimidazole Derivatives as Antimycobacterial Agents, Il Farmaco, 57, 259 (2002); https://doi.org/10.1016/S0014-827X(02)01218-1.

H. Minoura, S. Takeshita, M. Ita, J. Hirosumi, M. Mabuchi, I. Kawamura, S. Nakajima, O. Nakayama, H. Kayakiri, T. Oku, A. Ohkubo-Suzuki, M. Fukagawa, H. Kojo, K. Hanioka, N. Yamasaki, T. Imoto, Y. Kobayashi and S. Mutoh, Pharmacological Characteristics of a Novel Nonthiazolidinedione Insulin Sensitizer, FK614, Eur. J. Pharmacol., 494, 273 (2004); https://doi.org/10.1016/j.ejphar.2004.04.038.

G. Ayhan-Kilcigil, C. Kus, T. Çoban, B. Can-Eke and M. Iscan, Synth-esis and Antioxidant Properties of Novel Benzimidazole Derivatives, J. Enzyme Inhib. Med. Chem., 19, 129 (2004); https://doi.org/10.1080/1475636042000202017.

H. Nakano, T. Inoue, N. Kawasaki, H. Miyataka, H. Matsumoto, T. Taguchi, N. Inagaki, H. Nagai and T. Satoh, Synthesis and Biological Activities of Novel Antiallergic Agents with 5-lipoxygenase Inhibiting Action, Bioorg. Med. Chem., 8, 373 (2000); https://doi.org/10.1016/S0968-0896(99)00291-6.

S. Dixit, P. Sharma and N. Kaushik, Synthesis of Novel Benzimidazole Derivatives: As Potent Analgesic Agent, Med. Chem. Res., 22, 900 (2013); https://doi.org/10.1007/s00044-012-0083-1.

G. Mariappan, R. Hazarika, F. Alam, R. Karki, U. Patangia and S. Nath, Synthesis and Biological Evaluation of 2-Substituted Benzimidazole Derivatives, Arab. J. Chem., 8, 715 (2015); https://doi.org/10.1016/j.arabjc.2011.11.008.

S. Estrada-Soto, R. Villalobos-Molina, F. Aguirre-Crespo, J. Vergara-Galicia, H. Moreno-Diaz, M. Torres-Piedra and G. Navarrete-Vazquez, Relaxant Activity of 2-(Substituted phenyl)-1H-benzimidazoles on Isolated Rat aortic Rings: Design and Synthesis of 5-Nitro Derivatives, Life Sci., 79, 430 (2006); https://doi.org/10.1016/j.lfs.2006.01.019.

S.M. Badr, H.M. Eisa, A.M. Barghash and A.A. Farahat, Synthesis & Antimicrobial Activity of Certain Benzimidazole and Fused Benzimi-dazole Derivatives, Indian J. Chem., 49B, 1515 (2011).

Y. Radha, A. Manjula, B.M. Reddy and B.V. Rao, Synthesis and Biological Activity of Novel Benzimidazoles, Indian J. Chem., 50B, 1762 (2011).

M.A. Pagano, F. Meggio, M. Ruzzene, M. Andrzejewska, Z. Kazimierczuk and L.A. Pinna, 2-Dimethylamino-4,5,6,7-tetrabromo-1H-benzimi-dazole: A Novel Powerful and Selective Inhibitor of Protein Kinase CK2, Biochem. Biophys. Res. Commun., 321, 1040 (2004); https://doi.org/10.1016/j.bbrc.2004.07.067.

C. McBride, P. Renhowe, C. Heise, J. Jansen, G. Lapointe, S. Ma, R. Pineda, J. Vora, M. Wiesmann and C. Shafer, Design and Structure-Activity Relationship of 3-Benzimidazol-2-yl-1H-indazoles as Inhibitors of Receptor Tyrosine Kinases, Bioorg. Med. Chem. Lett., 16, 3595 (2006); https://doi.org/10.1016/j.bmcl.2006.03.069.

K. Starcevic, M. Kralj, K. Ester, I. Sabol, M. Grce, K. Pavelic and G. Karminski-Zamola, Synthesis, Antiviral and Antitumor Activity of 2-Substituted-5-amidino-benzimidazoles, Bioorg. Med. Chem., 15, 4419 (2007); https://doi.org/10.1016/j.bmc.2007.04.032.

Salahuddin, M. Shaharyar, A. Mazumder and M.M. Abdullah, Synthesis, Characterization and Antimicrobial Activity of 1,3,4-Oxadiazole bearing 1H-Benzimidazole Derivatives, Arab. J. Chem., 10, 503 (2017); https://doi.org/10.1016/j.arabjc.2012.10.010.

H. Kadri, C.S. Matthews, T.D. Bradshaw, M.F.G. Stevens and A.D. Westwell, Synthesis and Antitumour Evaluation of Novel 2-Phenyl-benzimidazoles, J. Enzyme Inhib. Med. Chem., 23, 641 (2008); https://doi.org/10.1080/14756360802205398.

M.-L. Wang and B.-L. Liu, Synthesis of 2-mercaptobenzimidazole from the Reaction of o-Phenylene Diamine and Carbon Disulfide in the Presence of Potassium Hydroxide, J. Chin. Inst. Chem. Eng., 38, 161 (2007); https://doi.org/10.1016/j.jcice.2007.01.003.

Synthesis and Evaluation of Novel Fluorobenzimidazole Derivatives as Antibacterial and Antifungal Agents

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