With an objective of synthesizing some novel, potent and broad spectrum antifungal activity having compounds, here some novel quinoline derivatives are reported. Initially 7-substituted-2-cholro-3-formylquinolines were prepared using well known Vilsemeir-Hack reagent method. These on microwave irradiation with 4M HCl yielded 7-substituted-2-hydroxy quinoline-3-carbaldehydes I(a, b), which on further treatment with different substituted hydrazides yielded the novel Schiff bases of quinoline II(a-f). The structure of all newly synthesized compounds was confirmed by spectral study such as IR, 1H NMR, 13C NMR and mass spectroscopy. All the synthesized compounds were screened for in-vitro antifungal activity by two fold serial dilution method using fluconazole as the standard drug. Compounds II a, II b and II d showed significant antioxidant activit

Kumar, M. R. Pradeep

Journal of Applied Pharmaceutical Research

English

Kumar, M. R. (M)

Neliti

Synthesis and Antifungal Activity Screening of Some Novel 7–substituted –2–hydroxy–quinoline Schiff Bases

M. R. Pradeep Kumar

Directory of Open Access Journals

Synthesis and antifungal activity screening of some novel 7–substituted –2–hydroxy–quinoline schiff bases

Journal of Applied Pharmaceutical Research (JOAPR)

5     *For Correspondence: pradeepmrpk@yahoo.co.in ©2016 The authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution (CC BY NC), which permits unrestricted use, distribution, and reproduction in any medium, as long as the original authors and source are cited. No permission is required from the authors or the publishers.                               Journal of Applied Pharmaceutical Research 2016, 4 (4): 5 – 9       SYNTHESIS AND ANTIFUNGAL ACTIVITY SCREENING OF SOME NOVEL 7–SUBSTITUTED –2–HYDROXY–QUINOLINE SCHIFF BASES  M. R. Pradeep Kumar Department of Pharmaceutical Chemistry, KLEU’s College of Pharmacy, Hubli – 580031, Karnataka  Article Information  ABSTRACT Received: 25th Aug 2016  With an objective of synthesizing some novel, potent and broad spectrum antifungal activity having compounds, here some novel quinoline derivatives are reported. Initially 7-substituted-2-cholro-3-formylquinolines were prepared using well known Vilsemeir-Hack reagent method. These on microwave irradiation with 4M HCl yielded 7-substituted-2-hydroxy quinoline-3-carbaldehydes I(a, b), which on further treatment with different substituted hydrazides yielded the novel Schiff bases of quinoline II(a-f). The structure of all newly synthesized compounds was confirmed by spectral study such as IR, 1H NMR, 13C NMR and mass spectroscopy. All the synthesized compounds were screened for in-vitro antifungal activity by two fold serial dilution method using fluconazole as the standard drug. Compounds II a, II b and II d showed significant antioxidant activity  Revised: 15th Sept 2016 Accepted: 27th Sept 2016    Keywords Quinoline, antifungal, two fold dilution, fluconazole, Schiff base   INTRODUCTION During last two decades, fungi have emerged as new life threatening agents, causing increased opportunistic infections in human and animals. In fact, overwhelming efforts of the medicinal chemists, it is not getting eradicated successfully. The unhygienic condition maintained by the people and dust induced infection being a prime reason for fungal infection to spread fast. Furthermore some of these organisms have earned a resistance to anti fungal drugs. In case of immuno compromised patients it spreads very fast. Thus there is a need to explore some novel antifungal agents. Quinoline ring system is a ubiquitous pharmacophore and an essential structural fragment of a large number of natural and synthetic compounds possessing versatile pharmacological activities like anti-inflammatory [1,2], antitubercular [3,4,5], antiviral [6], antimalarial [7,8], anticancer [9,10], antibacterial [11], antioxidant [12], tyrosine kinase inhibitor [13], anticonvulsant and antihypertensive [14] etc. These findings encouraged us for synthesizing some novel quinoline Schiff base compounds.   In this research work initially 7-substituted-2-cholro-3-formylquinolines on microwave irradiation with 4M HCl yielded 7-substituted-2-hydroxy quinoline-3-carbaldehydes I (a, b). IR spectra of these compounds showed characteristic peaks at around 3190 cm-1 (OH), 1680 cm-1 (C=O), 1620 cm-1 (C=N), Further a novel series of quinoline Schiff bases II (a-f) were synthesized by the reaction between 7-substituted-2-hydroxy quinoline-3-carbaldehydes I(a, b) and different hydrazides. IR spectra of these compounds showed characteristic peaks at around 3400 cm-1 (OH), 3100 cm-1 (NH), 1650 cm-1 (C=O), 1610 cm-1 (C=N).. 1H NMR spectra of these compounds showed characteristic peaks at around δ 8.3 and 12.25 ppm due to  protons of CH=N and OH respectively. 13 C NMR spectra of these compounds showed characteristic peaks at around δ 138 and 156 ppm due to  carbon of CH=N and C=O respectively.  MATERIALS AND METHOD General considerations The various chemicals used in the synthesis of the titled compounds were purchased from, Sigma-Aldrich Pvt Ltd, S.D. Fine Chem Pvt Ltd. Absolute ethanol and DMF utilized were purified according to the literature.  JOURNAL OF APPLIED PHARMACEUTICAL RESEARCH ISSN No. 2348 – 0335                                                                                             www.japtronline.com Pradeep Kumar M R Synthesis and antifungal activity screening of some novel 7-substituted -2-hydroxy-quinoline schiff bases     Journal of Applied Pharmaceutical Research  October – December 2016  Volume 4 Issue 4  6 Melting points of all synthesized compounds were determined by open capillary method and are uncorrected. FTIR spectra were recorded on Bruker Alpha-T by using KBr pellets. The 1HNMR were recorded on Bruker Avance II NMR 400 MHz instruments using DMSO as solvent and TMS as internal standard, chemical shifts are expressed as δ values (ppm). Elemental analysis was carried out for the synthesized compounds. All the physicochemical data are given in table 1.  Antifungal activity In vitro anti fungal activity of the synthesized compounds was evaluated by two fold serial dilution method25. Media used was Potato Dextrose Broth (PDB). Initially, the stock culture of Aspergillus niger, Aspergillus flavus, Aspergillus terrius and Candida albicans were revived by inoculating in broth media and grown at 370C for 48 hrs. The tubes of the above media PDB (5 ml) were prepared and each tube was added with compounds (10-500 μg) and inoculated with 100 μl of 48 hr old cultures. The control tubes with fluconazole and DMSO were also prepared. All the tubes were incubated at 370C for 48 h with constant shaking and the absorbance of biomass were measured at 660 nm using shimadzu UV-Visible spectrophotometer against autoclaved, uninoculated media as blank. The result of in vitro anti fungal activity is expressed as Minimum Inhibitory concentration (MIC). Compounds II a, II b and II d showed significant antifungal activity. Table 2 reveals antifungal activity (MIC) data for all the synthesized compounds.  Scheme: N ClCHO4M HClMW, 6 min N OHCHOSubstituted hydrazidesN OHCH=N-NH-R1Reflux, 4-6 hrI (a-b)II (a-f)II a =R II e = NCO  II c =   II b =NCOII f = II d =RNCONCOCSNH2CSNH2Where,EthanolNO2NO2RRRR1R1FFFNO2  Pradeep Kumar M R Synthesis and antifungal activity screening of some novel 7-substituted -2-hydroxy-quinoline schiff bases     Journal of Applied Pharmaceutical Research  October – December 2016  Volume 4 Issue 4  7 Table 1: Physico-chemical data of the synthesized compounds II (a-f) Compound Molecular  formula M.P°C %Yield Elemental Analysis Found (Calcd) %  Solubility C H N II a C16H11FN4O2 246-248 71 61.95 (61.92) 3.57 (3.51) 18.06 (18.03) DMSO II b C16H11FN4O2 258-260 68 61.95 (61.93) 3.57 (3.53) 18.06 (18.02) DMSO II c C11H9N5O3S 232-234 64 45.36 (45.32) 3.11 (3.08) 24.04 (24.91) DMSO II d C11H9FN4OS 274-276 76 49.99 (49.95) 3.43 (3.42) 21.20 (21.16)  DMSO II e C16H11 N5O4 224-226 70 56.98 (56.95) 3.29 (3.26) 20.76 (20.73) DMSO II f C16H11 N5O4 248-250 66 56.98 (56.97) 3.29 (3.27) 20.76 (20.75) DMSO  Table 2: Antifungal activity screening results of newly synthesized compounds II (a-f) Compound MIC values (μg/ ml) A.niger  A.flavus A.terrius C.albicans II a 25  50 12.5 50 II b 12.5  25 12.5 >100 II c 50  >100 50 >100 II d 50  100 12.5 25 II e 12.5  50 >100 12.5 II f 50  >100 100 12.5 DMSO (Solvent) --  -- -- -- Fluconazole 6.25  6.25 6.25 6.25  RESULTS General procedure for the synthesis of 7-substituted-2-hydroxyquinoline-3-carbaldehyde      I(a,b) A mixture of 7-substituted-2-chloro-3-formylquinolines (0.01 mol) and 4M HCl solution (30 ml) was subjected for MW irradiation (120 W) for 6 min. Yellow solid precipitated on cooling. This was poured into a beaker containing crushed ice (100 g), filtered, dried and recrystallised from glacial acetic acid. I a: IR (KBr) cm-1: 3192.54 (OH), 1681.35 (C=O), 1620.68 (C=N) . 1H NMR (400 MHz, DMSO-d6, δ ppm): 7.18 (d, 1H, C6-H of quinoline), 7.46-7.51 (m, 1H, C8-H of quinoline), 7.85 (d, 1H, C5-H of quinoline), 8.32 (s, 1H, C4-H of quinoline), 10.23 (s, 1H, CHO), 12.57 (s, 1H, OH). I b: IR (KBr) cm-1: 3189.11 (OH), 1684.76 (C=O), 1621.17 (C=N). 1H NMR (400 MHz, DMSO-d6, δ ppm): 7.21 (d, 1H, C6-H of quinoline), 7.49-7.57 (m, 1H, C8-H of quinoline), 7.85 (d, 1H, C5-H of quinoline), 8.29 (s, 1H, C4-H of quinoline), 10.46 (s, 1H, CHO), 12.29 (s, 1H, OH).  General procedure for the synthesis of compounds II (a-f) A mixture of compound I (a, b) (0.005 mol) in 25 ml of absolute ethanol, equimolar amount of substituted hydrazides (0.005 mol) and catalytic amount of glacial acetic acid were added. The mixture was refluxed for 6 h. Solid compound was obtained on cooling the reaction mixture. This was filtered, dried and recrystallized from ethanol and DMF mixture to get the final compounds   II (a-f). Pradeep Kumar M R Synthesis and antifungal activity screening of some novel 7-substituted -2-hydroxy-quinoline schiff bases     Journal of Applied Pharmaceutical Research  October – December 2016  Volume 4 Issue 4  8 II a: IR (KBr) cm-1: 3401.02 (OH), 3161.32 (NH), 1652.56 (C=O), 1607.89 (C=N). 1H NMR (400 MHz, DMSO-d6, δ ppm): 7.24 - 8.31 (m, 9H, C4, C5, C6, C8-H of quinoline, CH=N & C2, C3, C5, C6-H of pyridine), 12.02 (s, 1H, NH), 12.25 (s, 1H, OH). Mass (m/z): 310.68  II b: IR (KBr) cm-1: 3408.19 (OH), 3162.79 (NH), 1648.25 (C=O), 1612.31 (C=N), 1H NMR (400 MHz, DMSO-d6, δ ppm): 7.30 (s, 2H, C3 & C4-H of pyridine), 7.45 (s, 1H, C8-H of quinoline), 7.73 (s, 2H, C2 & C5-H of pyridine), 7.89 (s, 1H, C6-H of quinoline), 8.02 (s, 1H, C5-H of quinoline), 8.36 (s, 1H, CH=N), 8.59 (s, 1H, C4-H of quinoline), 11.66 (s, 1H, NH), 12.18 (s, 1H, OH).        13C NMR (400 MHz, DMSO-d6, δ ppm): 162.46 (quinoline- C2), 160.23 (C=O), 151.02 (quinoline C9), 144.22 (CH=N), 140.67 (pyridine- C4), 135.46 (quinoline- C4), 132.65 (quinoline- C7), 127.63 (pyridine- C3 and -C5), 125.32 (quinoline- C5), 123.16 (pyridine- C2 and -C6),  121.44 (quinoline- C8), 120.19 (quinoline- C6), 118.21 (quinoline- C10), 115.44 (quinoline- C3). Mass (m/z): 310.02  II c: IR (KBr) cm-1: 3409.14 (OH), 3104.41 (NH), 1681.74 (C=O), 1615.22 (C=N), 1H NMR (400 MHz, DMSO-d6, δ ppm): 7.31 (d, 1H, C8-H of quinoline), 7.43 (d, 1H, C6-H of quinoline), 7.59 (s, 1H, C5-H of quinoline), 8.32(s, 1H, C4-H of quinoline), 8.62(s, 2H, NH2), 8.78(s, 1H,  CH=N), 11.13 (s, 1H, NH), 12.17 (s, 1H, OH). Mass (m/z): 291.06  II d: IR (KBr) cm-1: 3416.10 (OH), 3133.21 (NH), 1659.04 (C=O), 1606.72 (C=N), 1H NMR (400 MHz, DMSO-d6, δ ppm): 7.29 (d, 1H, C8-H of quinoline), 7.47 (d, 1H, C6-H of quinoline), 7.59 (s, 1H, C5-H of quinoline), 8.24 (s, 1H, C4-H of quinoline), 8.59 (s, 2H, NH2), 8.77 (s, 1H,  CH=N), 11.54 (s, 1H, NH), 12.17 (s, 1H, OH). Mass (m/z): 264.85  II e: IR (KBr) cm-1: 3411.78 (OH), 3103.61 (NH), 1642.20 (C=O), 1610.32 (C=N), 1H NMR (400 MHz, DMSO-d6, δ ppm): 7.21 (s, 2H, C3 & C4-H of pyridine), 7.34 (s, 1H, C8-H of quinoline), 7.61 (s, 2H, C2 & C5-H of pyridine), 7.79 (s, 1H, C6-H of quinoline), 7.98 (s, 1H, C5-H of quinoline), 8.56 (s, 1H, CH=N), 8.81 (s, 1H, C4-H of quinoline), 11.39 (s, 1H, NH), 12.11 (s, 1H, OH).  Mass (m/z): 337.31 II f: IR (KBr) cm-1: 3418.76 (OH), 3146.22 (NH), 1644.82 (C=O), 1619.29 (C=N), 1H NMR (400 MHz, DMSO-d6, δ ppm): 7.44-8.85 (m, 9H, C4, C5, C6, C8-H of quinoline, CH=N & C2, C3, C5, C6-H of  pyridine), 11.18 (s, 1H, NH), 12.35 (s, 1H, OH).13C NMR (400 MHz, DMSO-d6, δ ppm): 162.44 (quinoline- C2), 161.53 (C=O), 151.32 (quinoline C9), 141.85 (CH=N), 139.88 (pyridine- C4), 136.66 (quinoline- C4), 131.04 (quinoline- C7), 128.11 (pyridine- C3 and -C5), 123.38 (quinoline- C5), 122.76 (pyridine- C2 and -C6),  121.02 (quinoline- C8), 120.77 (quinoline- C6), 118.59 (quinoline- C10), 116.63 (quinoline- C3). Mass (m/z): 337.57  DISCUSSION A novel series of quinoline Schiff bases II (a-f) have been synthesized by reacting 7-substituted/unsubstituted-2-hydroxy-3-formylquinolines I (a, b) with substituted hydrazides. The purity of the synthesized compounds was confirmed by TLC. The structure of all the newly synthesized compounds was confirmed by physicochemical and spectral data. All the compounds were screened for their antifungal activities using two fold serial dilution method, Among the series II (a-f), compound II a showed significant antifungal activity against A.terrius. Compound II b showed significant antifungal activity against A.niger and A.terrius Compound II d showed significant antifungal activity against A.terrius, Compounds II e and II f showed significant antifungal activity against C.albicans. Compounds II c has showed moderate antifungal activity against A.niger and A.terrius. Compounds II a, II b and II d containing fluorine at the 7th position of quinoline shown significant antifungal activity against the tested organisms  CONCLUSION In the series II (a-f) it is evidently observed that the antifungal activity of the compounds has been greatly influenced by the presence of fluorine as a substituent on the quinoline nucleus. Quinoline moiety and its Schiff bases do contribute for the observed activity but the presence of fluorine at 7th position of quinoline contributed for its significant antifungal activity. The preliminary antifungal activity screening result of these compounds depicted them as potential antifungal leads endowed with moderate to excellent activity. Further enhancement in the activity can be achieved by slight modifications in the ring substituent Pradeep Kumar M R Synthesis and antifungal activity screening of some novel 7-substituted -2-hydroxy-quinoline schiff bases     Journal of Applied Pharmaceutical Research  October – December 2016  Volume 4 Issue 4  9 ABBREVIATIONS  ACKNOWLEDGEMENT The authors are thankful to The Principal KLEU’s college of Pharmacy, Hubli and Principal SET’s college of Pharmacy, Dharwad for providing the necessary facilities to carry out this research work. We also thank The Director, SAIF, Punjab University, Chandigarh, Punjab, India and The Director, USIC, Karnataka University, Dharwad, India for providing spectral data.   CONFLICT OF INTEREST: No any conflict of interest  REFERENCES  1. Chen Y, Chen I.L, Lu C.M, Tzeng C.C, Tsao L.T, Wang J.P. Synthesis and anti-inflammatory evaluation of 4-anilinofuro[2,3-b] quinoline and 4-phenoxyfuro [2,3-b] quinoline derivatives. Bioorg Med Chem.,2004;12: 387-392. 2. Bawa S, Kumar S. Synthesis of schiff’s bases of 8-methyl tetrazolo [ 5-a] quinoline as potential anti inflammatory and antimicrobial agents. Ind J  Chem., 48B 2009;1:142-5.  3. de Souza M.V, Pais K.C, Kaiser C.R, Peralta M.A, Ferreira M.L, Lourenco M.C. Synthesis and in-vitro antitubercular activity of a series of quinoline derivatives. Bioorg & Med Chem.,2009;17: 1474-1480.  4. Pradeep Kumar M.R, Joshi S.D, Dixit S.R, Kulkarni V.H. Synthesis, antibacterial and antitubercular activities of some novel quinoline derivatives. Ind J Heterocycl Chem., 2014; 23: 353-358.  5. Lilienkampf A, Mao J, Wan B, Wang Y, Franzblau S.G, Kozikowski A.P. Structure-activity relationships for a series of quinoline-based compounds active against replicating and nonreplicating Mycobacterium tuberculosis. J Med Chem., 2009; 52:2109-2118.  6. Jamal M.A, Mohammed K, Manogaran P.S, Adnan A.B, El-Sayed O.A, Al-Hussein K,. Hassan Y.A, Al-Khodairy F.M. Evaluation of cytotoxic potential of newly synthesized antiviral aminopyrazoloquinoline derivatives. Int J Biomed Sci., 2007; 3: 194-198. 7. Pretorius S.I, Breytenbach W.J, de Kock C, Smith P.J, N'Da D.D. Synthesis, characterization and antimalarial activity of quinoline-pyrimidine hybrids. Bioorg & Med Chem., 2013; 21: 269-277.  8. Kaur K, Jain M, Reddy R.P, Jain R. Quinolines and structurally related heterocycles as antimalarials. Eur J Med Chem., 2010; 45: 3245-3264. 9. Vaidya A, Jain A.K, Kumar P, Kashaw S.K, Agrawal R.K .  Predicting anti-cancer activity of quinoline derivatives; CoMFA and CoMSIA approach. J Enzyme Inhib Med Chem., 2011; 26: 854-861. 10. Chen Y, Hung H, Lu C, Li K and  Tzeng C. Synthesis and anticancer evaluation of certain indolo[2,3-b] quinoline derivatives Bioorg & Med Chem., 2004;12:6539-6546.  11. Joshi S.D, Joshi A, Vagdevi H.M, Vaidya V.P, Gadaginamath G.S. Synthesis of some quinolinylpyeazoles as potential antibacterial and antitubercular agents. Ind J Heterocycl Chem., 2010; 19: 221-225. 12. Shirwaiker A, Rajendran K, Dinesh Kumar C. In vitro antioxidant studies of Annona squamosa Linn. Leaves. Ind. J. Expl. Biol., 2004; 42: 803-807.  13. Maguire M.P, Sheets K.R, McVety K, Spada A.P, Zilberstein A. A new series of PDGF receptor tyrosine kinase inhibitors: 3-substituted quinoline derivatives. J Med Chem 1994; 37: 2129-2137.  14. Ramaiah M. Anbala N.N, GunasekaranV and  Leonard J.T. Synthesis Anticonvulsant and Antihypertensive Activities of 8Substituted Quinoline Derivatives. Bio.l Pharm. Bull 2004; 27:1683-1687.  15. Jarrahpour A, Khalili D, De Clercq E, Salmi C, Brunel J.M. Synthesis, Antibacterial, Antifungal and Antiviral Activity Evaluation of Some New bis-Schiff Bases of isatin and Their Derivatives. Molecules 2007; 12: 1720-1730.  Term Expansion/ Full form UV Ultra violet FTIR Fourier Transform Infrared Radiation NMR Nuclear Magnetic Resonance TMS Tetra Methyl Silane DMSO Dimethyl sulfoxide nm Nanometer DMSO-d6 Deuterated Dimethyl sulfoxide MW irradiation Microwave irradiation 

https://www.neliti.com/publications/320067/synthesis-and-antifungal-activity-screening-of-some-novel-7substituted-2hydroxyq

Synthesis and antifungal activity screening of some novel 7–substituted –2–hydroxy–quinoline schiff bases

Abstract

Similar works

Full text

Available Versions

Neliti

Directory of Open Access Journals

Journal of Applied Pharmaceutical Research (JOAPR)