Development and evaluation of novel preservatives from simple organic acids 42

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1 3. Synthesis and antimicrobial evaluation of ferulic acid derivatives 3.1 Experimental All reagents and solvents used in study were of analytical grade and procured locally. The progress of the reaction was monitored by TLC and products were purified through recrystallization and purity of the compounds was checked by thin layer chromatography (TLC) performed on silica gel G coated plate. The spectral studies, IR and 1 H NMR were determined by standard methods. Infra red (IR) spectra were recorded on FTIR Bruker ATR instrument in cm H and 13 C nuclear magnetic resonance ( 1 H and 13 C NMR) spectra were determined using a Bruker Avance II 400 NMR spectrometer in appropriate deuterated solvents and are expressed in parts per million (δ, ppm) downfield from the internal standard TMS. NMR data are provided with multiplicity (s, singlet; d, doublet; t, triplet; m, multiplet) and number of protons. Mass spectra were taken on Bruker Compass Data Analysis 4.0 Mass spectrometer Procedure for the synthesis of 8-hydroxy quinoline esters of ferulic acid (1-8, 10, 11, 14) For preparation of ferulic acid chloride, thionyl chloride (0.3 mol) was added gradually to ferulic acid (0.25 mol) in a round bottom flask. After addition of thionyl chloride, the mixture was stirred for 4 h and heated to 80 0 C for 30 min in water bath and excess of thionyl chloride was removed by distillation. A solution of 8-hydroxy quinoline (0.05 mol) in ether (50 ml) was added to a solution of ferulic acid (0.05 mol) in ether (50 ml). The mixture was heated on water bath until no further evolution of hydrogen chloride was observed and completion of reaction was checked by single spot TLC. The mixture was cooled to room temperature and evaporation of solvent yielded the crude product which was purified by recrystallization with alcohol General procedure for the synthesis of amides/anilides of ferulic acid (15-38) The solution of corresponding amine /aniline (0.1 mol) in ether (50mL) was added drop wise to a solution of ferulic acid chloride (0.1 mol) in ether (50 ml) maintained at C temperature. The solution was stirred for 30 min and the precipitated amide was separated by filtration. The crude amide was recrystallized with alcohol. In case of anilides, the precipitated crude anilide was treated with 5% hydrochloric acid, 4% sodium carbonate and water to remove residual aniline and the resultant anilide was recrystallized with alcohol. 42

2 3.1.3 General procedure for the synthesis of esters of ferulic acid (9, 12 and 13) A mixture of ferulic acid (0.08 mol) and appropriate alcohol (0.74 mol) was heated under reflux in presence of sulphuric acid till the completion of reaction which was checked by single spot TLC. Then, the reaction mixture was poured in 200 ml ice cold water, neutralized with sodium bicarbonate solution followed by extraction of ester with ether (50 ml). The ether layer was separated, which on evaporation yielded the ester derivatives of ferulic acid In vitro antimicrobial activity The antimicrobial activity of the synthesized compounds was tested against Grampositive bacteria: Staphylococcus aureus MTCC 2901, Bacillus subtilis MTCC 2063, Gram negative bacterium: Escherichia coli MTCC 1652 and fungal strains: Candida albicans MTCC 227 and Aspergillus niger MTCC 8189 using tube dilution method (Cappucino and Sherman, 1999). Dilutions of test and standard compounds were prepared in double strength nutrient broth-i.p. (bacteria) or Sabouraud dextrose broth I.P. (fungi). The samples were incubated at 37 ºC for 24 h (bacteria), at 25 ºC for 7 d (A. niger), and at 37 ºC for 48 h (C. albicans), and the results were recorded in terms of minimum inhibitory concentration (MIC). 3.2 Results and discussion Chemistry Ferulic acid derivatives (1-38) were synthesized as outlined in Scheme 1. The physicochemical properties of the synthesized compounds are presented in Table 1. The structures of all the newly synthesized compounds were confirmed by the IR, 1 H NMR, 13 C NMR and mass analysis which were in full agreement with their structures. Intermediate. IR (ATR) cm -1 : 3620 (-H str., phenol), 1632 (C= str., acid chloride), 2937 (C-H str., aromatic), 1563 (C=C skeletal str., phenyl), 1684 (C=C str., alkene), 723 (C-Cl str., acid chloride). Compound 1. IR (ATR) cm -1 : 3591 (-H str., phenol), 1707 (C= str., ester), 2997 (C-H str., aromatic), 1545 (C=C skeletal str., phenyl), 1646(C=C str., alkene), 3063 (C-H str., Ar-CH 3 ). Compound 2. IR (ATR) cm -1 : 3601 (-H str., phenol), 1710 (C= str., ester), 3008 (C-H str., aromatic), 1544 (C=C skeletal str., phenyl), 1637 (C=C str., alkene), 1452 (ring str., quinoline), 754 (C-H out of plane bending, quinoline), 1683 (C=N str., quinoline), 3050 (C-H str., Ar-CH 3 ); 1 H (NMR, DMS, δ ppm): 3.52 (s, 3H, 43

3 CH 3 ), 8.00 (d, 1H, CH (C 3 ) of acrylate), 7.46 (d, 1H, CH (C 2 ) of acrylate), (m, 9H, ArH); 13 C NMR (DMS-d 6 ): , , , , , , ; MS ES+ (ToF): m/z 322 [M + + 1]. Compound 3. IR (ATR) cm -1 : 3608 (-H str., phenol), 1707 (C= str., ester), 2998 (C-H str., aromatic), 1545 (C=C skeletal str., phenyl), 1645(C=C str., alkene), 1464 (CH 2 scissoring, cyclohexane), 1037 (ring str., cyclohexane), 3038 (C-H str., Ar- CH 3 ). CH R-H CR H 2 S 4 9, 12, 13 C N N SCl 2 CCl R-H CR 1, 3-8, 10, 11, 14 2 CNHR NH 33, 35, 36, R-NH 2 H 2 N CH SCl 2 R 7 NH 2 CCl R 3 HN 37 C N R 6 R 5 R 4 C H N R 3 R 4 R R 7 R 6 Scheme 1: Scheme for synthesis of amide, anilide and ester derivatives of ferulic acid 44

4 Comp. R Comp. R Comp. R 1 NH CH N C 4 H C 2 H 5 13 C 3 H Comp. R R 3 R 4 R 5 R 6 R H H H H H 16 - CH 3 H H N 2 H 17 - Cl H N 2 H H 18 - H Cl H H H 19 - Cl H H H H 20 - H CH 3 H H H 21 - CH 3 H H H H 22 - CH 3 CH 3 H H H 23 - CH 3 H CH 3 H H 24 - CH 3 H H CH 3 H 25 - N

5 Comp. R R 3 R 4 R 5 R 6 R H H N 2 H H 27 - H N 2 H H H 28 - CH 3 H H H H 29 H Cl F H H 30 - H H CH 3 H H 31 H H CH 3 H H 32 F H - H H C 3 H C 4 H N Compound 4. IR (ATR) cm -1 : 3620 (-H str., phenol), 1704 (C= str., ester), 2955 (C-H str., aromatic), 1534 (C=C skeletal str., phenyl), 1646(C=C str., alkene), 3367 (C-H str., alkane), 3029 (C-H str., Ar-CH 3 ). Compound 5. IR (ATR) cm -1 : 3607 (-H str., phenol), 1709 (C= str., ester), 2941 (C-H str., aromatic), 1536 (C=C skeletal str., phenyl), 1638(C=C str., alkene), 3301 (C-H str., alkane), 3029 (C-H str., Ar-CH 3 ). Compound 6. IR (ATR) cm -1 : 3648 (-H str., phenol), 1694 (C= str., ester), 3029 (C-H str., aromatic), 1544 (C=C skeletal str., phenyl), 1656 (C=C str., alkene), 3077 (C-H str., Ar-CH 3 ), 1335 (N 2 sym. str., Ar-N 2 ); 1 H (NMR, DMS, δ ppm):

6 (s, 3H, CH 3 ), 8.10 (d, 1H, CH (C 3 ) of acrylate), 6.91 (d, 1H, CH (C 2 ) of acrylate), (m, 7H, ArH). Compound 7. IR (ATR) cm -1 : 3620 (-H str., phenol), 1707 (C= str., ester), 2957 (C-H str., aromatic), 1546 (C=C skeletal str., phenyl), 1646 (C=C str., alkene), 2957 (C-N 2 str., C 6 H 4 N 2 ), 3093 (C-H str., Ar-CH 3 ). Compound 8. IR (ATR) cm -1 : 3619 (-H str., phenol), 1747 (C= str., ester), 3062 (C-H str., aromatic), 1513 (C=C skeletal str., phenyl), 1615 (C=C str., alkene), 3109 (C-H str., Ar-CH 3 ); 1 H (NMR, DMS, δ ppm): 3.73 (s, 6H, CH 3 ), 5.93 (d, 1H, CH (C 3 ) of acrylate), 5.80 (d, 1H, CH (C 2 ) of acrylate), (m, 3H, ArH). Compound 10. IR (ATR) cm -1 : 3618 (-H str., phenol), 1705 (C= str., ester), 2947 (C-H str., aromatic), 1548 (C=C skeletal str., phenyl), 1644(C=C str., alkene), 2995 (C-H str., alkane), 3076 (C-H str., Ar-CH 3 ). Compound 11. IR (ATR) cm -1 : 3618 (-H str., phenol), 1709 (C= str., ester), 2947 (C-H str., aromatic), 1545 (C=C skeletal str., phenyl), 1637 (C=C str., alkene), 2900 (C-H str., alkane), 3074 (C-H str., Ar-CH 3 ). Compound 12. IR (ATR) cm -1 : 3606 (-H str., phenol), 1708 (C= str., ester), 2932 (C-H str., aromatic), 1545 (C=C skeletal str., phenyl), 1646(C=C str., alkene), 3048 (C-H str., alkane), 3078 (C-H str., Ar-CH 3 ). Compound 13. IR (ATR) cm -1 : 3622 (-H str., phenol), 1708 (C= str., ester), 2917 (C-H str., aromatic), 1535 (C=C skeletal str., phenyl), 1627 (C=C str., alkene), 3025 (C-H str., alkane), 3025 (C-H str., Ar-CH 3 ). Compound 15. IR (ATR) cm -1 : 3627 (-H str., phenol), 1735 (C= str., 2 0 amide), 2932 (C-H str., aromatic), 1537 (C=C skeletal str., phenyl), 1631 (C=C str., alkene), 3050 (C-H str., Ar-CH 3 ). Compound 16. IR (ATR) cm -1 : 3646 (-H str., phenol), 1717 (C= str., 2 0 amide), 2951 (C-H str., aromatic), 1519 (C=C skeletal str., phenyl), 1646 (C=C str., alkene), 3041 (C-H str., Ar-CH 3 ). Compound 18. IR (ATR) cm -1 : 3672 (-H str., phenol), 1700 (C= str., 2 0 amide), (C= str., ester), 2965 (C-H str., aromatic), 1559 (C=C skeletal str., phenyl),725 (C- Cl str., aromatic), 1728 (C=N str., quinoline), 3070 (C-H str., Ar-CH 3 ). Compound 19. IR (ATR) cm -1 : 3666 (-H str., phenol), 1715 (C= str., 2 0 amide), 2974 (C-H str., aromatic), 1537 (C=C skeletal str., phenyl), 1641 (C=C str., alkene), 750 (C-Cl str., aromatic), 3077 (C-H str., Ar-CH 3 ). 47

7 Compound 20. IR (ATR) cm -1 : 3601 (-H str., phenol), 1750 (C= str., 2 0 amide), 2965 (C-H str., aromatic), 1540 (C=C skeletal str., phenyl), 1682 (C=C str., alkene), 3054 (C-H str., Ar-CH 3 ). Compound 24. IR (ATR) cm -1 : 3645 (-H str., phenol), 1711 (C= str., 2 0 amide), 2937 (C-H str., aromatic), 1548 (C=C skeletal str., phenyl), 1701 (C=C str., alkene), 3163 (C-H str., CH 3 aromatic), 3059 (C-H str., Ar-CH 3 ). Compound 25. IR (ATR) cm -1 : 3619 (-H str., phenol), 1702 (C= str., 2 0 amide), 2896 (C-H str., aromatic), 1547 (C=C skeletal str., phenyl), 1694 (C=C str., alkene), 3002 (C-N 2 str., C 6 H 4 N 2 ), 3054 (C-H str., Ar-CH 3 ). Compound 26. IR (ATR) cm -1 : 3556 (-H str., phenol), 1725 (C= str., 2 0 amide), 3072 (C-H str., aromatic), 1545 (C=C skeletal str., phenyl), 1692 (C=C str., alkene); 2983 (C-H str., Ar-CH 3 ); 1 H (NMR, DMS, δ ppm): 3.59 (s, 3H, CH 3 ), 7.57 (d, 1H, CH (C 3 ) of acrylate), 6.95 (d, 1H, CH (C 2 ) of acrylate), (m, 7H, ArH), 9.94 (s, 1H, NH of amide); 13 C NMR (DMS-d 6 ): , , , , , , Compound 28. IR (ATR) cm -1 : 3679 (-H str., phenol), 1707 (C= str., ester), 2971 (C-H str., aromatic), 1545 (C=C skeletal str., phenyl), 1694 (C=C str., alkene), 2995 (C-H str., alkane), 3089 (C-H str., Ar-CH 3 ). Compound 29. IR (ATR) cm -1 : 3566 (-H str., phenol), 1692 (C= str., 2 0 amide), 3047 (C-H str., aromatic), 1555 (C=C skeletal str., phenyl), 1647 (C=C str., alkene); 3079 (C-H str., Ar-CH 3 ); 1042 (C-F str., C 6 H 3 ClF), 732 (C-Cl str., C 6 H 3 ClF); 1 H (NMR, DMS, δ ppm): 3.35 (s, 3H,CH 3 ), 7.53 (d, 1H, CH (C 3 ) of acrylate), 7.37 (d, 1H, CH (C 2 ) of acrylate), (m, 6H, ArH), 8.63 (s, 1H, NH of amide). Compound 30. IR (ATR) cm -1 : 3576 (-H str., phenol), 1736 (C= str., 2 0 amide), 3029 (C-H str., aromatic), 1540 (C=C skeletal str., phenyl), 1695 (C=C str., alkene); 3074 (C-H str., Ar-CH 3 ), 2911 (C-H str., alkane); 1 H (NMR, DMS, δ ppm): 3.56 (s, 3H, CH 3 ), 7.54 (d, 1H, CH (C 3 ) of acrylate), 6.47 (d, 1H, CH (C 2 ) of acrylate), (m, 7H, ArH), 2.42 (s, 3H, aromatic CH 3 ); 13 C NMR (DMS-d 6 ): 53.73, 57.11, , , , , , , ; MS ES+ (ToF): m/z 284 [M + + 1]. Compound 32. IR (ATR) cm -1 : 3607 (-H str., phenol), 1693 (C= str., ester), 2962 (C-H str., aromatic), 1548 (C=C skeletal str., phenyl), 1693 (C=C str., alkene), 710 (C-F str., aromatic), 3012 (C-H str., Ar-CH 3 ). 48

8 Compound 33. IR (ATR) cm -1 : 3605 (-H str., phenol), 1638 (C= str., 2 0 amide), 3062 (C-H str., aromatic), 1552 (C=C skeletal str., phenyl), 1707 (C=C str., alkene), 3094 (C-H str., Ar-CH 3 ), 2900 (C-H str., alkane); 1 H (NMR, DMS, δ ppm): 3.39 (s, 3H, CH 3 ), 7.49 (d, 1H, CH (C 3 ) of acrylate), 7.38 (d, 1H, CH (C 2 ) of acrylate), (m, 8H, ArH), 8.55 (s, 1H, NH of amide), 3.99 (d, 2H, CH 2 of benzyl. Compound 34. IR (ATR) cm -1 : 3605 (-H str., phenol), 1694 (C= str., ester), 2956 (C-H str., aromatic), 1547 (C=C skeletal str., phenyl), 1644 (C=C str., alkene), 1340 (ring str., quinoline), 741 (C-H out of plane bending, quinoline), 3021 (C-H str., Ar-CH 3 ). Compound 36. IR (ATR) cm -1 : 3619 (-H str., phenol), 1693 (C= str., ester), 2987 (C-H str., aromatic), 1514 (C=C skeletal str., phenyl), 1693 (C=C str., alkene), 3066 (C-H str., Ar-CH 3 ). Compound 37. IR (ATR) cm -1 : 3627 (-H str., phenol), 1709 (C= str., 2 0 amide), 3043 (C-H str., aromatic), 1537 (C=C skeletal str., phenyl), 1747 (C=C str., alkene), 3090 (C-H str., Ar-CH 3 ), 3584 (N-H str., morpholine), 1088 (C--C str., morpholine); 1 H (NMR, DMS, δ ppm): 3.41 (s, 3H, CH 3 ), 7.04 (d, 1H, CH (C 3 ) of acrylate), 6.88 (d, 1H, CH (C 2 ) of acrylate), (m, 3H, ArH), 8.55 (s, 1H, NH of amide), (t, 8H, CH 2 of morpholene); 13 C NMR (DMS-d 6 ): , , , , , , , Compound 38. IR (ATR) cm -1 : 3620 (-H str., phenol), 1693 (C= str., ester), 2945 (C-H str., aromatic), 1514 (C=C skeletal str., phenyl), 1693 (C=C str., alkene), 3008 (C-H str., Ar-CH 3 ) In vitro antimicrobial activity The synthesized ferulic acid derivatives were evaluated for their in vitro antibacterial activity against S. aureus, B. subtilis, E. coli and antifungal activity against C. albicans and A. niger by tube dilution method. From the recorded MIC values (Table 2), it was observed that compound 37 was found to be most active against E. coli, having MIC value Compound 1 was found to be most active against S. aureus, B. subtilis C. albicans and A. niger having MIC values in each case. In general, the results of MBC/MFC studies (Table 3) revealed that the synthesized compounds were bacteriostatic and fungistatic in action as their MFC and MBC values were 3-fold higher than their MIC values (a drug is considered to be 49

9 bacteriosatic/fungistatic when its MFC and MBC values are 3- fold higher than its MIC value) (Rodriguez-Arguelles et al., 2005). Table 1. Physicochemical properties of synthesized ferulic acid derivatives (1-38) Comp. Mol. Formula M. Wt. m.p. ( o C) R f Value * % Yield 1 C 16 H 15 N C 19 H 15 N C 16 H C 14 H C 13 H C 17 H C 16 H 13 N C 20 H C 11 H C 15 H C 14 H C 12 H C 13 H C 16 H C 16 H 15 N C 17 H 16 N C 16 H 13 ClN C 16 H 14 ClN C 16 H 14 ClN C 17 H 17 N C 17 H 17 N C 18 H 19 N C 18 H 19 N C 18 H 19 N C 16 H 14 N C 16 H 14 N C 16 H 14 N C 17 H 17 N C 16 H 13 ClFN C 17 H 17 N C 17 H 17 N C 16 H 16 FN C 17 H 17 N C 20 H 17 N C 13 H 17 N C 14 H 19 N C 14 H 17 N C 16 H 14 N * TLC mobile phase: Benzene: Chloroform (7:3) 50

10 Table 2. Antimicrobial activity of ferulic acid derivatives (1-38) Comp. Minimum inhibitory concentration (µm/ml) E. coli S. aureus B. subtilis A. niger C. albicans Std * * * ** ** * Norfloxacin ** Fluconazole Std. = Standard 51

11 3.2.3 Structure activity relationship From the antimicrobial activity results of the synthesized ferulic acid derivatives, the following structure activity relationship can be drawn: Esters of ferulic acid were more potent antimicrobial agents than amides and anilides. The high antimicrobial activity of esters is also evidenced by the results of Mahiwal et al In case of antimicrobial activity of synthesized ferulic acid derivatives against S. aureus, B. subtilis, C. albicans and A. niger p-amino ester of ferulic acid (1) was found to be most potent antimicrobial agent, which indicated that esters having electron donating substituents on p-position of phenyl nucleus will be more potent antimicrobial agents against S. aureus, B. subtilis, C. albicans and A. niger. Results of antibacterial screening of synthesized ferulic acid derivatives against E.coli indicated that the amide derivative of morpholine (37) was found to be the most potent antibacterial agent. The morpholine having the ether oxygen withdraws electron density from nitrogen and makes it most potent antibacterial agent against E.coli. This fact is also in accordance with the study of Sharma et al The anilide derivatives of ferulic acid have no effect on the antimicrobial activity as none of the anilide derivatives showed significant activity against the proposedtested microbial strains. From the abovementioned results, it can be concluded that different structural requirements are necessary for different ferulic acid derivatives to become active against different microbial targets. This is in accordance with the results obtained by Sortino et al The abovementioned findings are summarized in Fig. 1. C N Morpholine Increased antibacterial activity against E. coli CH CR NH 2 Increased antimicrobial activity against S. aureus, C. albicans and A. niger CNH R Anilides Do not shows the antimicrobial activity against microbial strains Fig 1. Structure activity relationship of the synthesized ferulic acid derivatives. 52

12 Table 3. Minimum bactericidal/fungicidal (MBC/MFC in µm/ml) of synthesized ferulic acid derivatives against different microorganisms S. No. E. coli S. aureus B. subtilis A. niger C. albicans 1 >0.18 >0.18 >0.18 >0.18 > >0.16 >0.16 >0.16 >0.16 > >0.18 >0.18 >0.18 >0.18 > >0.20 >0.20 >0.20 >0.20 > >0.21 >0.21 >0.21 >0.21 > >0.18 >0.18 >0.18 >0.18 > >0.16 >0.16 >0.16 >0.16 > >0.15 >0.15 >0.15 >0.15 > >0.24 >0.24 >0.24 >0.24 > >0.19 >0.19 >0.19 >0.19 > >0.20 >0.20 >0.20 >0.20 > >0.23 >0.23 >0.23 >0.23 > >0.21 >0.21 >0.21 >0.21 > >0.19 >0.19 >0.19 >0.19 > >0.19 >0.19 >0.19 >0.19 > >0.15 >0.15 >0.15 >0.15 > >0.14 >0.14 >0.14 >0.14 > >0.17 >0.17 >0.17 >0.17 > >0.17 >0.17 >0.17 >0.17 > >0.18 >0.18 >0.18 >0.18 > >0.17 >0.17 >0.17 >0.17 > >0.17 >0.17 >0.17 >0.17 > >0.17 >0.17 >0.17 >0.17 > >0.17 >0.17 >0.17 >0.17 > >0.16 >0.16 >0.16 >0.16 > >0.16 >0.16 >0.16 >0.16 > >0.16 >0.16 >0.16 >0.16 > >0.18 >0.18 >0.18 >0.18 > >0.16 >0.16 >0.16 >0.16 > >0.18 >0.18 >0.18 >0.18 > >0.17 >0.17 >0.17 >0.17 > >0.17 >0.17 >0.17 >0.17 > >0.18 >0.18 >0.18 >0.18 > >0.16 >0.16 >0.16 >0.16 > >0.21 >0.21 >0.21 >0.21 > >0.20 >0.20 >0.20 >0.20 > >0.19 >0.19 >0.19 >0.19 > >0.17 >0.17 >0.17 >0.17 >0.17 Std * * * ** ** * Norfloxacin ** Fluconazole 53

13 3.3 Conclusion A series of ferulic acid derivatives (1-38) was synthesized and evaluated in vitro for their antimicrobial activity against different Gram positive and Gram negative bacterial and as well fungal strains by tube dilution method. Results of antimicrobial screening indicated that esters and amides of ferulic acid were more potent than anilides and compound 1 was the most active antimicrobial agent (MIC = µm/ml). Results of MBC/MFC studies indicated that the synthesized compounds were bacteriostatic and fungistatic in action. 3.4 References: Cappucino JG, Sherman N. Microbiology-a laboratory manual, Addison Wesley, California, 1999; 263. Mahiwal K, Kumar P, Narasimhan B. Synthesis, antimicrobial evaluation, ot-qsar and mt-qsar studies of 2-amino benzoic acid derivatives. Med. Chem. Res. 2012; 21(3): Pharmacopoeia of India. Controller of Publications, Ministry of Health Department, Govt. of India, New Delhi. 2007; vol. I: pp. 37. Rodriguez-Arguelles MC, Lopez-Silva EC, Sanmartin J, Pelagatti P, Zani F. Copper complexes of imidazole-2-, pyrrole-2- and indol-3-carbaldehyde thiosemicarbazones: Inhibitory activity against fungi and bacteria. J. Inorg. Biochem. 2005; 99: Sharma P, Rane N, Gurram VK. Synthesis and QSAR studies of pyrimido[4,5- d]pyrimidine-2, 5-dione derivatives as potential antimicrobial agents. Bioorg. Med. Chem. Lett. 2004; 14: Sortino M, Delgado P, Jaurez S, Quiroga J, Abonia R, Insuasey B, et al. Synthesis and antifungal activity of (Z)-5-arylidenerhodanines. Bioorg. Med. Chem. Lett. 2007; 15: