SYNTHESIS AND ANTIMICROBIAL ACTIVITIES OF NEW 1,2,4- TRIAZOLES, MANNICH BASES, CONAZOLES, AND FLUOROQUINOLONES

Abstract

Triazoles are heterocyclic compounds which have been of interest in the development of novel compounds with antidepressant, anti-inflammatory, analgesic, antibacterial, antimycobacterial, antifungal, antiviral, anticancer, and other activities. In this article, a series of fluorine- and piperazine-containing some novel biologically active 1,2,4-triazole-3-one derivatives were synthesized by the Mannich reaction of triazole intermediates. The structures for novel synthesized compounds were elucidated using elemental analysis and FT IR, ¹³C NMR, ¹H NMR, EI MS techniques. These compounds were investigated in vitro for their antimicrobial properties and several compounds have fungicidal activity against Candida albicans and Saccharomyces cerevisiae. And also some of the compounds exhibited excellent activity on Mycobacterium smegmatis, a nonpigmented fast-rising mycobacterium, at the concentration of <1 μg/mL is better than standard drug streptomycin.

Keywords

• 1,2,4-triazole
• piperazine
• conazole
• mannich base
• biological activity

References

1. Akbas E, Berber I, Sener A, Hasanov B. Synthesis and antibacterial activity of 4-benzoyl-1-methyl-5-phenyl-1H-pyrazole-3-carboxylic acid and derivatives. Il Farmaco. 2005;60(1):23–26. DOI: 10.1016/j.farmac.2004.09.003.
2. Rawal RK, Phabhakar YS, Kati SB, De Clercq E. 2-(Aryl)-3-furan-2-ylmethyl-thiazolidin-4-ones as selective HIV-RT inhibitors. Bioorg. Med. Chem. 2005;13:6771-6776. DOI: 10.1016/j.bmc.2005.07.063.
3. Bonde CG, Gaikwad NJ. Synthesis and preliminary evaluation of some pyrazine containing thiazolines and thiazolidinones as antimicrobial agents. Bioorg. Med. Chem. 2004;12(9):2151-2161. DOI: 10.1016/j.bmc.2004.02.024.
4. Rawal RK, Tripathi R, Kati SB, Pannecouque C, De Clercq E. Design, synthesis, and evaluation of 2-aryl-3-heteroaryl-1,3-thiazolidin-4-ones as anti-HIV agents. Bioorg. Med.Chem. 2007;15(4):1725-1731. DOI: 10.1016/j.bmc.2006.12.003.
5. Dixit PP, Patil VJ, Nair PS, Jain S, Sinha N, Arora SK. Synthesis of 1-[3-(4-benzotriazol-1/2-yl-3-fluorophenyl)- 2-oxo-oxazolidin-5-ylmethyl]-3-substituted-thiourea derivatives as antituberculosis agents. Eur. J. Med. Chem. 2006;41:423–428. DOI: 10.1016/j.ejmech.2005.12.005.
6. Hu C, Solomon VR, Cano P Lee HA. 4-aminoquinoline derivative that markedly sensitizes tumor cell killing by Akt inhibitors with a minimum cytotoxicity to non-cancer cells, Eur. J. Med. Chem. 2010;45:705-709. DOI: 10.1016/j.ejmech.2009.11.017.
7. Anderegg TR, Jones RN, Preliminary susceptibility testing guidelines for AZD2563, a long-acting oxazolidinone. Inter. J. Antimic. Agents. 2004;23:6–10. DOI: 10.1016/j.ijantimicag.2003.05.007.
8. Zhu W, Wang J, Wang S, Gu Z, Aceña JL, Izawa K, Liu H, Soloshonok VA. Recent advances in the trifluoromethylation methodology and new CF3-containing drugs. J. Fluorine Chem. 2014;167:37–54. DOI: 10.1016/j.jfluchem.2014.06.026.

9. Wang J, Sánchez-Roselló M, Aceña JL, del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H. Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001-2011). Chem. Rev. 2014;114(4):2432–2506. DOI: 10.1021/cr4002879.
10. Abdel-Megeed MF, Badr BE, Azaam MM, El-Hiti GA. Synthesis and Antimicrobial Activities of Diphenyl(Arylamino)(1-Phenyl-3-(Pyridin-2-Yl)-1H-Pyrazol-4-Yl)Methylphosphonates. Phosphorus Sulfur Silicon Relat. Elem. 2012;187:1462–1468. DOI: 10.1080/10426507.2012.690117.
11. Corr MJ, O’Hagan D. Fluorosugars: An improved synthesis of the 2,3,4-trideoxy-2,3,4-trifluoro hexose analogue of D-glucose. J. Fluorine Chem. 2013;155:72-77. DOI: 10.1016/j.jfluchem.2013.06.003.
12. Kirk KL. Fluorine in medicinal chemistry: Recent therapeutic applications of fluorinated small molecules. J. Fluorine Chem. 2006;127(8): 1013–1029. DOI: 10.1016/j.jfluchem.2006.06.007.
13. Li QH, Zhang G, Ding Y, et al. Synthesis and anti-tumor activities of novel triazole Schiff-base derivatives, J. Southwest Univ. Natl. Sci. Ed. 2014;40:826-832. DOI: 10.3969/j.issn.1003-4271.2014.06.05
14. Yuguo Z, Wei X, Qingqing G, Ping L, Zhenchao W, Kai Y. Synthesis and Antitumor Activity of 5, 6-2H-[1, 2, 4]-Triazolo [3, 4-b][1, 3, 4] thiadiazine Derivatives. CHINESE JOURNAL OF ORGANIC CHEMISTRY. 2011;31(6):912–916. URL: http://sioc-journal.cn/Jwk_yjhx/EN/abstract/abstract340136.shtml.
15. Yin K, Jiang L, Zhou H, Huang Y, Xiang J. Synthesis and insecticidal activity of 2-perfluoroalkyl-substituted or glucopyranosyl-substituted 2, 4-dihydro-1, 2, 4-triazole-3-thione Schiff base. Chinese journal of organic chemistry. 2008;28(6):1016–1023. URL: http://sioc-journal.cn/Jwk_yjhx/EN/abstract/abstract336787.shtml.
16. Feng ZX, Zhang WN, Zhou YJ, et al. Synthesis and antifungal activities of 1-[2- (N-methyl-N-substituted-benzyl)amino-2-(4-tert-butylphenyl)ethyl]-1H-1,2,4- triazoles, Chem. J. Chin. Univ. 2000;21:1221–1226. URL: http://en.cnki.com.cn/Article_en/CJFDTOTAL-GDXH200008015.htm.
17. Xu JY, Zeng Y, Jiang B, et al. Synthesis, anti-inflammatory activities and SAR studies of 1,5-diaryl substituted-1,2,4-triazoles, Chin. J. Med. Chem. 2008;18:321–328
18. Zhao XY, Gong YX, Zhang ZW, et al. Synthesis and plant growth regulating activity of N-5-(3-carboxy-1,2,4-triazolyl)-N0 -aroyl urea, Chin. J. Appl. Chem. 2003;20:594–596.
19. Jiang DH, Huang M. Design and synthesis of thieno[3,2-d]pyrimidine derivatives containing a piperazine unit as anticancer agents, Chem. Reag. 2012;34:797– 799. URL: http://en.cnki.com.cn/Article_en/CJFDTOTAL-HXSJ201209012.htm.
20. Wu Q, Wang ZC, Wei X, Xue W. Synthesis and antibacterial activities of 1- substituted-4-[5-(4-substitutedphenyl)-1,3,4-thiadiazol-2-sulfonyl]piperazine derivatives, Chin. J. Synth. Chem. 2014;22:429–434. DOI: 10.3969/j.issn.1005-1511.2014.04.001.
21. Li GY, Ysn SG, Jiang S, et al. Synthesis of piperazine derivatives containing pyridinemethyl/thiazolemethyl and their biological activities, Chin. J. Org. Chem. 2008;28:2001–2006. URL: http://sioc-journal.cn/Jwk_yjhx/EN/Y2008/V28/I11/2001.
22. Sahooa S, Pranesh PK, Mahendra KCB, et al. Synthesis and Biological Activity of Certain Mannich Bases Derivatives from 1, 2, 4-Triazoles, Iranian Journal of Pharmaceutical Sciences. 2013;9(4):51-60. URL:http://www.ijps.ir/article_10248_b02d56dcd5b30e0eabfb136e9369ef80.pdf.
23. Wang Y, Xu K, Bai G, et al. Synthesis and antifungal activity of novel triazole compounds containing piperazine moiety, Molecules. 2014;19:1133-11340. DOI:10.3390/molecules190811333.
24. Foks H, Janowiec M, Zwolska Z, Augustynowicz-Kopec´ E. Synthesis and tuberculostatic activity of some 2-piperazinmethylene derivatives 1,2,4-triazole-3- thiones, Phosphorus Sulfur Silicon Relat. Elem. 2005;180:537–543. DOI: 10.1080/104265090517280.
25. Kouznetsov VV, Gomez-Barrio A. Recent developments in the design and synthesis of hybrid molecules basedon aminoquinoline ring and their antiplasmodial evaluation. Eur. J. Med. Chem. 2009;44(8):3091-3113. DOI: doi:10.1016/j.ejmech.2009.02.024.
26. Basoglu S, Demirbas A, Ulker S, Karaoglu SA, Demirbas N. Design, Synthesis And Biological Activities Of Some 7-Aminocephalosporanic Acid Derivatives. Eur. J. Med. Chem. 2013;69:622-631. URL: http://dx.doi.org/10.1016/j.ejmech.2013.07.040.
27. Bayrak H, Demirbas A, Karaoglu SA, Demirbas N. Synthesis of some new 1, 2, 4-triazoles, their Mannich and Schiff bases and evaluation of their antimicrobial activities. Eur. J. Med. Chem. 2009;44(3):1057-1066. DOI: 10.1016/j.ejmech.2008.06.019.
28. Zhao YJ, Wei W, Su ZG, Ma GH. Poly(ethylene glycol) prodrug for anthracyclines via N-Mannich base linker: Design, synthesis and biological evaluation. Int. J. Pharm. 2009;379(1):90–99. DOI: 10.1016/j.ijpharm.2009.06.013.
29. Gayniyat K, Wilie IE, Oluwakemi O. Synthesis of Mannich bases: 2-(3- Phenylaminopropionyloxy)-benzoic acid and 3-Phenylamino-1-(2, 4, 6-trimethoxy-phenyl)-propan-1- one, their toxicity, ionization constant, antimicrobial and antioxidant activities. Food Chem. 2014;165:515-521. DOI: 10.1016/j.foodchem.2014.05.119.
30. Fekner T, Baldwin JE, Adlington RM, Fardeau S, Jones TW, Prout CK, Schofield CJ. Syntheses of (6S)-cephalosporins from 6-aminopenicillanic acid. Tetrahedron. 2000;56: 6053–6074. URL: http://dx.doi.org/10.1016/s0040-4020(00)00486-5.
31. Dassonville-Klimpt A, Audic N, Sasaki A, Pillon M, Baudrin E, Mullié C, Sonnet P. Synthesis and antibacterial activity of catecholate–ciprofloxacin conjugates. Bioorg. Med. Chem. 2014;22:4049–4060. DOI: 10.1016/j.bmc.2014.05.067.
32. Foroumadi A, Oboudiat M, Emami S, Karimollah A, Saghaee L, Moshafi MH, Shafiee A. Synthesis and antibacterial activity of N-[2-[5- (methylthio)thiophen-2-yl]-2-oxoethyl] and N-[2-[5-(methylthio)thiophen- 2-yl]-2-(oxyimino) ethyl]piperazinyl quinolone derivatives. Bioorg. Med. Chem. 2006;14:3421-3427. DOI: 10.1016/j.bmc.2005.12.058.
33. National Committee for Clinical Laboratory Standards. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. 3rd ed., approved standard. Villanova (PA): National Committee for Clinical Laboratory Standards, 1993; NCCLS document no. M7-A3;13(25):1-32.