Journal of Chemical and Pharmaceutical Research

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1 Available on line Journal of Chemical and Pharmaceutical Research ISSN No: CODEN(USA): JCPRC5 J. Chem. Pharm. Res., 2011, 3(2): Antifungal activity studies of some mannich bases carrying nitrofuran moiety M. K. Shivananda * and Shet Prakash M Department of Post-Graduate Studies & Research in Chemistry, University College of Science, Tumkur University, Tumkur, Karnataka State, INDIA ABSTRACT A series of 3-substituted-4-(5-nitro-2-furfurylidene)amino-5-mercapto-1,2,4-triazoles 3 and their Mannich bases have been synthesized. The structures of these Schiff bases and Mannich bases were confirmed on the basis of elemental analysis, 1 H NMR and mass spectral data. The above compounds were also screened for their antifungal activity against C.albicans. Keywords: Mannich bases, nitrofurans, synthesis, characterization, antifungal activity. INTRODUCTION Mannich reactions have become important tools for the synthesis of novel compounds. Mannich bases can either be directly employed or used as intermediates in chemical synthesis. They are shown to display a broad spectrum of pharmacological activities such as antibacterial, antiviral, antifungal, antimalarial and CNS depressant activities[1-3]. Many Mannich bases of 1,2,4- triazoles carrying N-methylpiperazine moiety possess protozoacidal and bactericidal activities[4]. Mannich bases of conjugated styryl ketones and related compounds have been shown to exhibit activity against P 388 lymphocytic leukemia[5]. Besides, the ubiquitous presence of the piperazine nucleus in cardiovascular drugs such as Prazosin[6], Lidoflazine[7] and Urapidil[8] encouraged us to undertake the synthesis of Mannich bases carrying N- methylpiperazine moiety. Further, many nitrofuran derivatives have been shown to possess promising biocidal activities[9-10]. 303

2 In view of these observations, synthesis of a series of Mannich bases of 3-substituted-4-(5-nitro- 2-furfurylidene)amino-1,2,4-triazol-5-thiones (3) was undertaken 11. In this paper, we wish to report the antifungal study of these Mannich bases. EXPERIMENTAL SECTION Melting points were determined in open capillary tubes and are uncorrected. IR spectra (cm -1 ) were recorded in KBr pellets on FT-IR Spectrophotometer and NMR on Bruker (300 MHz-FT NMR ). Standard chemical shift values are given in δ ppm. Compounds were checked for their purity by TLC on silica gel plates and spots were visualized in iodine vapour. Scheme 1 Synthesis of 4-(5-nitro-2-furfurylidene)amino-5-mercapto-3-alkyl-1,2,4-triazoles 4 An equimolecular mixture of suitably substituted aminomercaptotriazoles 2 (0.01 mol) and 5- nitro-2-furfuraldehyde diacetate (2.43g, 0.01 mol) in absolute ethanol (20 ml) was treated with concentrated sulphuric acid (0.5 ml) and heated under reflux for about 1-2 hr. On cooling the 304

3 reaction mixture, a solid product separated out. It was collected by filtration and recrystallized from suitable solvents. Synthesis of 1-aminomethyl-3-substituted-4-(5-nitro-2-furfurylidene)-1,2,4-triazo-5-thiones 5a-n A mixture of Schiff base 4 (0.01 mol) and formaldehyde (40%, 1.5 ml) in ethanol (20 ml) was stirred at room temperature with a solution of primary/secondary amine (0.01 mol) in ethanol (10 ml) for 30 minutes. The solid product that separated on standing for an hour was collected by filtration, washed with ethanol and dried. It was recrystallized from ethanol to yield the title compounds 5. The characterization data of these compounds are given in Table-1. SCHEME-1 The physical characterization data of all the compounds has been summarized in Table1. Table 1-Physical characterization data of compounds Compd R >NR 1 R 11 Yield (%) M.P. ( 0 C) Mol formula 5a H morpholine C 12 H 14 N 6 O 4 S 5b H 2-Aminopyridine C 13 H 12 N 7 O 3 S 5c H 3-Cl-4-F-Aniline C 14 H 10 ClFN 6 O 3 S 5d Me morpholine C 13 H 16 N 6 O 4 S 5e Me 2-Aminopyridine C 14 H 13 N 7 O 3 S 5f Me 3-Cl-4-F-Aniline C 15 H 12 ClFN 6 O 3 S 5g Me N-methylpiperazino C 14 H 19 N 7 O 3 S 5h Et morpholino C 14 H 18 N 6 O 4 S 5i Et 2-Aminopyridino C 15 H 15 N 7 O 3 S 5j Et 3-Cl-4-F-Aniline C 16 H 14 ClFN 6 O 3 S 5k Et N-methylpiperazine C 15 H 21 N 7 O 3 S 5l Pr morpholine C 15 H 20 N 6 O 4 S 5m Pr 2-Aminopyridine C 16 H 17 N 7 O 3 S 5n Pr 3-Cl-4-F-Aniline C 17 H 16 ClFN 6 O 3 S Elemental Analysis Found(Calcd.) %C %H %N (42.6) (4.14) (24.85) (45.0) (3.46) (28.32) (42.37) (2.52) (21.19) (44.32) (4.55) (23.86) (46.80) (3.62) (27.30) (43.85) (2.92) (20.46) (46.03) (5.21) (26.85) (45.90) (4.92) (22.95) (48.26) (4.02) (26.27) (45.23) (3.30) (19.79) (47.49) (5.54) (22.59) (47.37) (5.26) (22.11) (49.61) (46.52) (4.39) 3.59 (3.65) (25.32) (19.16) Antifungal activity All the newly synthesized Mannich bases 5 were screened for their antifungal activities against C.albicans by disc-diffusion method[13]. Their diameters of zone of inhibition (in mm) were 305

4 measured at 5 µg/ml concentration. Nitrofurazone and Fluconazole were used as standard drugs for comparison. The results are given in Table 2. Table 2-Antifungal activity of compounds Compound Zone of inhibition in (mm) at 5 µg /ml concn.( C. albicans) 5a 12 5b 09 5c 14 5d 13 5e 09 5f 17 5g 10 5h 13 5i 10 5j 14 5k 07 5l 09 5m 05 5n 15 Nitrofurazone (Standard) 20 Fluconazole (Standard) 12 RESULTS AND DISCUSSION 3-Alkyl-4-amino-5-mercapto-1,2,4-triazoles 2 were synthesized according to the literature methods[12]. The aminomercaptotriazoles 2 were condensed with nitrofurfural diacetate 1 to obtain Schiff bases 3. These Schiff bases 3 were then reacted with primary or secondary amines in presence of formaldehyde in ethanol medium.(scheme-1). 2-Aminopyridine, 3-chloro-4- fluoroaniline and two secondary amines namely, morpholine and N-methylpiperazine were used for the Mannich reaction. The structures of Mannich bases were confirmed on the basis of nitrogen analysis, IR, NMR and mass spectral data. In the NMR spectrum of Mannich base 5g, the NCH 2 - proton signals appeared as two multiplets at δ 2.45 and 2.9 accounting for the presence of eleven protons, while the signal due to methyl protons appeared as a singlet at δ The methyl proton signal of triazole ring appeared as a singlet at δ 2.3 integrating for three protons. The signal due to N=CH- proton was seen as a singlet δ In the mass spectrum of Mannich bases 5e and 5n, molecular ion peaks were not observed. However, common fragmentation pathways are observed in the mass spectra of both the compounds. The molecular ion underwent McLafferty rearrangement to give fragment ions of formaldehyde anils. Similar fragmentation also produced fragments ions of Schiff bases, which further underwent loss of 5-nitro-2-furonitrile to yield ions at m/z 143 and 115 respectively. The peak at m/z 143 observed in case of 5n further underwent a second McLafferty rearrangement to produce an ion at m/z 115. The synthesized compounds were screened for their antifungal activity. The activity was compared with that of standard drug Fluconazole. The screening data indicate that compounds 306

5 5c, 5d, 5f, 5h, 5j and 5n were found to possess greater degree of antifungal activities compared to Fluconazole. Compound 5f showed highest degree of antifungal activity. However, all the compounds showed lesser degree of antifungal activity compared to Nitrofurazone. It is thus concluded that compounds 5c, 5d, 5f, 5h, 5j and 5n stand to be promising antifungal agents and hence it is worth pursuing these compounds for further pharmacological investigations. CONCLUSION The present work describes a simple approach for the synthesis of Mannich bases carrying nitrofuran substituents. The pharmacological profile of the synthesized compounds revealed that the antifungal activity of some of the Mannich bases was greater than that of the standard drug and hence deserve further in depth pharmacological investigations. Acknowledgement The authors are thankful to Head, RSIC, CDRI Lucknow and Head, RSIC, IIT Madras for providing micro-analysis and spectral data. REFERENCES [1] M.A. Ghannoun, W.R. Brown, M. Valmas,; Microbias. 1985, 42, 211. [2] B.B. Gordon, S.Ireland.; Aust.J.Chem., 1988, 41, [3] V.S. Rajendra, V.K. Kaushal.; Ind.J.Chem., 1988, 27B, 698. [4] B.S. Holla, M.K. Shivananda, S. Shenoy, G. Antony.; Boll.Chim. Farmaceutico, 1998, 136, [5] J.R. Dimmock, M. Chamankkah, T.M. Allen, S. Halleran.; Pharmazie, 1995, 50, 221. [6] Scriabine et al.; Experientia, 1968, 24, 1150; Cohen.; J.Clin.Pharmacol., J.New Drugs, 1970, 10, 408. [7] Schaper et al.; J.Pharmacol.Exp.Ther., 1966, 152, 265. [8] V.W. Schoetensack, P. Bischler, E.Ch.Dittmann and V. Steinijans, Arzneim-Forsch., 1977, 27(11), [9] M.C. Dodd, W.B. Stillman.; J.Pharmacol.Exp.Therap., 1944, 82, 11. [10] D. Nardi, E. Massarani, A. Tajana, L. Degen, M.J. Magistretti.; J.Med.Chem., 1967, 10, 530. [11] B.S. Holla, M.T. Padmaja, M.K. Shivananda, P.M. Akberali.; Ind.J.Het.Chem., 1997, 6, [12] K.S. Dhaka, J. Mohan, V.K. Chadha, H.K. Pujari.; Indian J.Chem., 1974, 12B, 288. [13] R. Cruickshank, J.P. Duguid, B.P. Marmion, R.H.A. Swain.; Medical Microbiology, 1975, Vol. II (Churchill Livingstone, London and New York),