Share This Article:

Synthesis of Pyrroles and Condensed Pyrroles as Anti-Inflammatory Agents with Multiple Activities and Their Molecular Docking Study

Abstract Full-Text HTML XML Download Download as PDF (Size:1539KB) PP. 49-96
DOI: 10.4236/ojmc.2015.54005    3,656 Downloads   4,805 Views   Citations

ABSTRACT

We herein disclose a series of novel pyrrole derivatives as well as fused pyrrolopyridines 6a,b and 7a,b, pyrrolopyrazoles 8a, b, pyrrolo[2,3-d]pyrimidine derivatives 10a-d, 12a,b, 14a,b, 18a,b, 20a,b, 21a,b, 22a,b, 23a,b, 24a,b, 31a,b, 36a,b, 40a,b, pyrrolo[1,2,6]thiadiazine derivatives 19a,b, pyrrolotriazolopyrimidines 25a,b, 26a,b, 27a,b and 28a,b, pyrrolo[2,3-d][1,2,3]triazine derivatives 32a,b and pyrrolo[2,3-d][1,3]oxazine derivatives 39a,b as novel compounds. All compounds were evaluated for their anti-inflammatory, analgesic (compared to the reference drug Indomethacin) and antimicrobial activities (compared to the reference drug Ampicillin and Fluconazole). Compounds 4d, 5b-d, 6a,b, 9c,d, 10d, 12ab, 13b, 19a,b, 21b, 23b, 31a,b, 38b and 40a were found to be the most active anti-inflammatory drugs exhibiting potency ranging from 1 - 1.01 compared to the reference drug indomethacin. In addition to docking study of these highly active twenty compounds against the active site of cyclooxygenase-2 enzyme (COX-2), among the tested compounds, compounds 5d, 9d, 11b, 12a, 13b and 32a showed multiple activities; anti-inflammatory, analgesic and anti-bacterial activities.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Sarg, M. , Koraa, M. , Bayoumi, A. and Gilil, S. (2015) Synthesis of Pyrroles and Condensed Pyrroles as Anti-Inflammatory Agents with Multiple Activities and Their Molecular Docking Study. Open Journal of Medicinal Chemistry, 5, 49-96. doi: 10.4236/ojmc.2015.54005.

References

[1] Hatamjafari, F. and Montazeri, N. (2009) Three-Component Process for the Synthesis of Some Pyrrole Derivatives under Microwave Irradiation. Turkish Journal of Chemistry, 33,797-802.
[2] Gajera, R. V. (2010) Synthesis and Physicochemical Studies of Some Molecules of Meducinal Interest. PhD. Thesis, Saurashtra University, Rajkot, p. 23.
[3] Idhayadhulla, A., Kumar, R. S. and Abdul Nasser, A. J. (2011) Synthesis, Characterization and Antimicrobial Activity of New Pyrrole Derivatives. Journal of the Mexican Chemical Society, 55, 218-223.
[4] Mohamed, M. S., Mostafa, A. G. and Abd El-hameed, R. H. (2012) Evaluation of the Anti-Inflammatory Activity of Novel Synthesized Prrole, Pyrrolopyrimidine and Spiropyrrolopyrimidne Derivatives. Pharmacophore, 3, 44-54.
[5] Dannhardt, G., Kiefer, W., Kramer, G., Maehrlein, S., Nowe, U. and Fiebich, B. (2000) The Pyrrole Moiety as a Template for COX-1/COX-2 Inhibitors. European Journal of Medicinal Chemistry, 35, 499-510. http://dx.doi.org/10.1016/S0223-5234(00)00150-1
[6] Bijander, K., Vinit, R., Arvind, K., and Vaishali, S. (2012) Anti-Inflammatory Activity of 1,3,4-Oxadiazole Derivatives Compound. International Journal of Current Pharmaceutical Research, 4, 9-14.
[7] Rachel, C., Monica, K. (2015) In Vitro Anti-Oxidant and Anti-Inflammatory Activity of Newly Synthesized Schiff Bases Derived from 2-Aminothiazole Derivatives. Indo American Journal of Pharmaceutical Research, 5, 2078-2088.
[8] Grillo, M. P. and Hua, F. (2003) Identification of Zomepirac-S-acyl-glutathione in Incubations with Rat Hepatocytes and in Vivo in Rat Bile. Drug Metabolism and Disposition, 31, 1429-1436.
[9] Lessigiarska, I., Nankov, A., Bocheva, A., Pajeva, I. and Bijev, A. (2005) 3D-QSAR and Preliminary Evaluation of Anti-Inflammatory Activity of Series of N-Pyrrolylcarboxylic Acids. IL Farmaco, 60, 209-218. http://dx.doi.org/10.1016/j.farmac.2004.11.008
[10] Harrak, Y., Rosell, G., Daidone, G., Plescia, S., Schillaci, D. and Pujol, M.D. (2007) Synthesis and Biological Activity of New Anti-Inflammatory Compounds Containing the 1,4-Benzodioxine and/or Pyrrole System. Bioorganic & Medicinal Chemistry, 15, 4876.
http://dx.doi.org/10.1016/j.bmc.2007.04.050
[11] Ushiyama, S., Yamada, T., Murakami, Y., Kumakura, S., Inoue, S., Suzuki, K., Nakao, A., Kawara, A. and Kimura, T. (2008) Preclinical Pharmacology Profile of CS-706, a Novel Cyclooxygenase-2 Selective Inhibitor, with Potent Antinociceptive and Anti-Inflammatory Effects. European Journal of Pharmacology, 578, 76. http://dx.doi.org/10.1016/j.ejphar.2007.08.034
[12] Mohamed, M.S., Kamel, R. and Fatahala, S.S. (2011) Synthesis of New Pyrroles of Potential Anti-Inflammatory Activity. Archiv der Pharmazie, 344, 830-839.
http://dx.doi.org/10.1002/ardp.201100056
[13] Pham, V.C., Shin, J.S., Choi, M.J., Kim, T.W., Lee, K., Kim, K.J., Huh, G., Kim, J., Choo, D.J., Lee, K.T. and Lee, J.Y. (2012) Biological Evaluation and Molecular Docking Study of 3-(4-Sulfamoylphenyl)-4-phenyl-1H-pyrrole- 2,5-dione as COX-2 Inhibitor. Bulletin of the Korean Chemical Society, 33, 721-724. http://dx.doi.org/10.5012/bkcs.2012.33.2.721
[14] Parmar, K., Sutariya, S., Shukla, M. and Goswami, K. (2012) Synthesis and Antimicrobial Activity of Substituted 2H-Pyrrole-2-ones Derivatives Based on 1-N-phenyl-3-phenyl-4-formyl Pyrazole (PFP). Journal of Chemical and Pharmaceutical Research, 4, 3478-3482.
[15] Joshi, S.D., More, U.A., Pansuriya, K., Aminabhavi, T.M. and Gadad, A.K. (2013) Synthesis and Molecular Modeling Studies of Novel Pyrrole Analogues as Antimycobacterial Agents. Journal of Saudi Chemical Society.
[16] Jana, G.H., Jain, S., Arora, S.K. and Sinha, N. (2006) Corrigendum to “Synthesis of Some Diguanidino 1-Methyl-2,5- Diaryl-1H-Pyrroles as Antifungal Agents” [Bioorg. Med. Chem. Lett. 15 (2005) 3592-3595]. Bioorganic & Medicinal Chemistry Letters, 16, 751.
http://dx.doi.org/10.1016/j.bmcl.2005.10.095
[17] Raimondi, M.V., Cascioferro, S., Schillaci, D. and Petruso, S. (2006) Synthesis and Antimicrobial Activity of New Bromine-Rich Pyrrole Derivatives Related to Monodeoxypyoluteorin. European Journal of Medicinal Chemistry, 41, 1439-1445. http://dx.doi.org/10.1016/j.ejmech.2006.07.009
[18] Biava, M., Porretta, G.C., Poce, G., Logu, A.D., Meleddu, R., Rossi, E.D., Manettic, F. and Botta, M. (2009) 1,5-Di- aryl-2-ethyl Pyrrole Derivatives as Antimycobacterial Agents: Design, Synthesis, and Microbiological Evaluation. European Journal of Medicinal Chemistry, 44, 4734-4738. http://dx.doi.org/10.1016/j.ejmech.2009.06.005
[19] Mehta, S. (2013) Synthesis and Biological Activity of Pyrrole and Pyrrolidine Compounds from 4-Chloro-2-hydroxy- benzoic Acid Hydrazide. International Journal of Pharmaceutical Research and Bio-Science, IJPRBS, 2, 382.
[20] Ghorab, M.M., Heiba, H.I., Hassan, A.A., Abd El-Aziz, A.B. and El-Gazzar, M.G. (2011) Antimicrobial Evaluation of Novel Pyrrole, Pyrazole, Pyrimidine and Pyrrolo [2,3-d]-Pyrimidine Derivatives Bearing Sulfonamide Moiety. The Journal of American Science, 7, 1063-1073.
[21] Nicolaou, K.C., Simmons, N.L., Chen, J.S., Haste, N.M. and Nizet, V. (2011) Total Synthesis and Biological Evaluation of Marinopyrrole A and Analogs. Tetrahedron Letters, 52, 2041-2043.
http://dx.doi.org/10.1016/j.tetlet.2010.09.059
[22] Idhayadhulla, A., Kumar, R.S., Abdul Nasser, A.J. and Manilal, A. (2012) Synthesis and Antimicrobial Activity of Some New Pyrrole Derivatives. Bulletin of the Chemical Society of Ethiopia, 26, 429-435. http://dx.doi.org/10.4314/bcse.v26i3.12
[23] Varaprasad, C.V., Ramasamy, K.S., Girardet, J.L., Gunic, E., Lai, V., Zhong, W., An, H. and Hong, Z. (2007) Synthesis of Pyrrolo[2,3-d]pyrimidine Nucleoside Derivatives as Potential Anti-HCV Agents. Bioorganic Chemistry, 35, 25- 34. http://dx.doi.org/10.1016/j.bioorg.2006.07.003
[24] Dodonova, J., Uogintaite, I., Masevicius, V. and Tumkevicius, S. (2010) Palladium-Catalyzed Reaction of Methyl 5-Amino-4-chloro-2-methylthiopyrrolo[2,3-d]-pyrimidine-6-carboxylate with Arylboronic Acids. Synthesis of 1,3,4,6- Tetraazadibenzo[cd,f]-azulene Heterocyclic System. Chemistry of Heterocyclic Compounds, 46, 1122-1126. http://dx.doi.org/10.1007/s10593-010-0636-5
[25] Hilmy, K.M.H., Soliman, D.H., Shahin, E.B.A. and Abd Alhameed, R. (2012) Synthesis and Molecular Modeling Study of Novel Pyrrole Schiff Bases as Anti-HSV-1 Agents. Life Science Journal, 9, 736-745.
[26] de Courcy, B., Piquemal, J., Garbay, C. and Gresh, N. (2010) Polarizable Water Molecules in Ligand-Macromolecule Recognition. Impact on the Relative Affinities of Competing Pyrrolopyrimidine Inhibitors for FAK Kinase. Journal of the American Chemical Society, 132, 3312.
http://dx.doi.org/10.1021/ja9059156
[27] Shamsuzzaman, Siddiqui, T., Alam, M.G. and Dar, A.M. (2015) Synthesis, Characterization and Anticancer Studies of New Steroidal Oxadiazole, Pyrrole and Pyrazole Derivatives. Journal of Saudi Chemical Society, 19, 387-391. http://dx.doi.org/10.1016/j.jscs.2012.04.009
[28] Idhayadhulla, A., Kumar, R.S., Abdul Nasser, A.J. and Manilal, A. (2013) Synthesis of Some New Pyrrole and Pyridine Derivatives and their Antimicrobial, Anticancer Activities. International Journal of Biological Chemistry, 7, 15- 26. http://dx.doi.org/10.3923/ijbc.2013.15.26
[29] Kalgutkar, A.S., Crews, B.C., Rowlinson, S.W., Marnett, A.B., Kozak, K.R., Remmel, R.P. and Marnett, L.J. (2000) Biochemically Based Design of Cyclooxygenase-2 (COX-2) Inhibitors: Facile Conversion of Nonsteroidal Antiinflammatory Drugs to Potent and Highly Selective COX-2 Inhibitors. Proceedings of the National Academy of Sciences of the United States of America, 97, 925-930.
http://dx.doi.org/10.1073/pnas.97.2.925
[30] Zarghi, A., Javid, F.S., Ghodsi, R., Dadress, O.G., Daraie, B. and Hedayati, M. (2011) Design, Synthesis and Biological Evaluation of New 5,5-Diarylhydantoin Derivatives as Selective Cyclooxygenase-2 Inhibitors. Scienta Pharmaceutica, 79, 449-460. http://dx.doi.org/10.3797/scipharm.1104-20
[31] Etcheverry, S.B., Barrio, D.A., Cortizo, A.M. and Williams, P.A. (2002) Three New Vanadyl(IV) Complexes with Non-Steroidal Anti-Inflammatory Drugs (Ibuprofen, Naproxen and Tolmetin). Bioactivity on Osteoblast-Like Cells in Culture. Journal of Inorganic Biochemistry, 88, 94-100. http://dx.doi.org/10.1016/S0162-0134(01)00368-3
[32] Fernandes, E., Costa, D., Toste, S.A., Lima, J.L.F.C. and Reis, S. (2004) In Vitro Scavenging Activity for Reactive Oxygen and Nitrogen Species by Nonsteroidal Anti-Inflammatory Indole, Pyrrole, and Oxazole Derivative Drugs. Free Radical Biology and Medicine, 37, 1895-1905.
http://dx.doi.org/10.1016/j.freeradbiomed.2004.09.001
[33] Ghoneim, A.A. (2009) A Clean Procedure for Synthesis of Phenylquinoline Derivatives. Oriental Journal of Chemistry, 25, 449-504.
[34] Kotb, E.R., El-Hashash, M.A., Salama, M.A., Kalf, H.S., Abdel Wahed, N.A.M. (2009) Synthesis and Reactions of Some Novel Nicotinonitrile Derivatives for Anticancer and Antimicrobial Evaluation. Acta Chimica Slovenica, 56, 908-919.
[35] Carpenter, C.A., Kenar, J.A. and Price, N.P.J. (2010) Preparation of Saturated and Unsaturated Fatty Acid Hydrazides and Long Chain C-Glycoside Ketohydrazones. Green Chemistry, 12, 2012-2018.
http://dx.doi.org/10.1039/c0gc00372g
[36] Chavan, H.V., Bandgar, B.P., Adsul, L.K., Dhakane, V.D., Bhale, P.S., Thakare, V.N. and Masand, V. (2013) Design, Synthesis, Characterization and Anti-Inflammatory Evaluation of Novel Pyrazole Amalgamated Flavones. Bioorganic & Medicinal Chemistry Letters, 23, 1315-1321.
http://dx.doi.org/10.1016/j.bmcl.2012.12.094
[37] Kumar, S.T., Kanti, BT., Liaquat, A. and Biswapati, M. (2003) Anti-Inflammatory and Anti-Platelet Aggregation Activity of Human Placental Extract. Acta Pharmacologica Sinica, 24, 187-192.
[38] Winter, C.A., Risley, E.A. and Nuss, G.W. (1962) Carrageenin-Induced Edema in Hind Paw of the Rat as an Assay for Antiinflammatory Drugs. Experimental Biology and Medicine, 111, 544-547.
http://dx.doi.org/10.3181/00379727-111-27849
[39] Sammour, O.A., Al-Zuhair, H.H. and El-Sayed, M. I. (1998) Inhibitory Effect of Liposome-Encapsulated Piroxicam on Inflammation and Gastric Mucosal Damage. Pharmazeutische Industrie, 60, 1084-1087.
[40] Khalifa, M.M. and Abdelbaky, N.A. (2007) Synthesis of New Imidazolyl Acetic Acid Derivatives as Potential Anti- Inflammatory Agents. Az. J. Pharm. Sci., 35, 22-30.
[41] Hemamalini, K., Naik, K.O. and Ashok, P. (2010) Anti-Inflammatory and Analgesic Effect of Methanolic Extract of Anogeissus acuminata Leaf. International Journal of Pharmaceutical and Biomedical Research, 1, 98-101.
[42] Curfman, G.D., Morrissey, S. and Drazen, J.M. (2005) Expression of Concern: Bombardier et al., “Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis,” N Engl J Med 2000;343:1520-8. The New England Journal of Medicine, 353, 2813-2814. http://dx.doi.org/10.1056/NEJMe058314
[43] Metwally, K.A., Yaseen, S.H., Lashine, E.M., El-Fayomi, H.M. and El-Sadek, M.E. (2007) Non-Carboxylic Analogues of Arylpropionic Acids: Synthesis, Anti-Inflammatory Activity and Ulcerogenic Potential. European Journal of Medicinal Chemistry, 42, 152-160.
http://dx.doi.org/10.1016/j.ejmech.2006.09.001
[44] Koster, R., Anderson, M. and Beer, D. (1959) Acetic Acid for Analgesic Screening. Federation Proceedings, 18, 412.
[45] Narayana, B., Raj, K.K.V., Ashalatha, B.V. and Kumari, N.S. (2005) Synthesis of Some New 2-(6-Methoxy-2-Naph- thyl)-5-Aryl-1,3,4-Oxadiazoles as Possible Non-steroidal Anti-inflammatory and Analgesic Agents. Archiv der Pharmazie, 338, 373-377. http://dx.doi.org/10.1002/ardp.200500974
[46] Sharma, K.K., Saikia, R., Kotoky, J., Kalita, J.C. and Das, J. (2011) Evaluation of Antidermatophytic Activity of Piper betle, Allamanda cathertica and Their Combination: An in Vitro and in Vivo Study. International Journal of PharmTech Research, 3, 644-651.

  
comments powered by Disqus

Copyright © 2019 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.