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Unusual Formation of N-hydroxy-3,3-dimethyl-2,6-diarylpiperidin-4-one and its Thiosemicarbazide Derivative-Synthesis and Antimicrobial Activity

N-Hydroxy-3,3-dimethyl-2,6-diarylpiperidin-4-one과 그것의 Thiosemicarbazide 유도체의 특이한 합성 및 항균 활성

  • Gopalakrishnan, M. (Synthetic Organic Chemistry Laboratory, Department of Chemistry, Annamalai University) ;
  • Sureshkumar, P. (Synthetic Organic Chemistry Laboratory, Department of Chemistry, Annamalai University) ;
  • Thanusu, J. (Synthetic Organic Chemistry Laboratory, Department of Chemistry, Annamalai University) ;
  • Kanagarajan , V. (Synthetic Organic Chemistry Laboratory, Department of Chemistry, Annamalai University)
  • Published : 2008.10.20

Abstract

Keywords

N-Hydroxy-3,3-dimethyl-2,6-diarylpiperidin-4-one Thiosemicarbazones ; m-chloroperbenzoic Acid ; Stereochemistry ; Antimicrobial

INTRODUCTION

Organo-sulfur compounds dominate much of synthetic, analytical and medicinal chemistry. A better understanding of their biological activity can be derived from their oxidation mechanisms. It is widely accepted that the prerequisite for thio compounds to express their physiological effects is through S-Oxygenation.1 Oxidation of organo-sulfur compounds appear to be involved in many cellular functions2 including the reductive degradation of polypeptide hormones and proteins, regulation of protein synthesis, maintenance of intracellular redox potential, protection of cell from oxidative damage etc., The chemistry of hydrazine derivatives such as thiosemicarbazide and its hydrazones is of immense interest owing to their wide synthetic and analytical applications and biological activities.3 Biological activities of thiosemicarbazide derivatives include: antithyroid activity,4 which leads to a disruption of the pituitary-thyroid hormonal regulatory system, effective antidotes to paraquat toxicity5 in an HL 60 cell culture system, anticonvulsant effect,6 pesticidal and fungicidal effect,7 tuberculastatic,8 bactericide,9 CNS depressant activity,10 treatment of liver diseases and disorders,11 plant-growth promoting agents,12 treatment13 of influenza, small pox, protozoa, tumors etc.

Heterocyclic ring systems having piperidine-4- one nucleus have aroused great interest in the past and recent years due to their wide variety of biological properties such as antiviral, antitumour,14,15 central nervous system,16 local anesthetic,17 anticancer,18 and antimicrobial activity19 and their derivative piperidine are also biologically important and act as neurokinin receptor antagonists,20 analgesic and anti-hypertensive agents.21

In addition, hydroxylamines have been reported as anti-bacterial, antifungal and antileukemic agents. N-Hydroxy urea was one of the effective antineouplasmic agent22 and ciclopirox has broad- spectrum antifungal activity.23

In recent years there has been a great deal of interest in exploiting more than one proximal functional groups for designing novel structures capable of performing a variety of functions. In the course of broad programme in developing biologically active molecules, we have recently reported the synthesis of 2,6-diarylpiperidin-4-one derivatives and evaluated their biological importance.24,25 Aiming at extending our knowledge in structure–activity relationship, we considered that it is valuable to synthesis a system which unites biolabile functional groups like thiosemicarbazide and hydroxyl amines into 3,3-dimethyl-2,6-diarylpiperidin-4-one nucleus which together will give a compact structure of N-Hydroxy-3,3-dimethyl-2,6-diarylpiperidin-4-one thiosemicarbazones. The influence of some structural variations by varying the substituent at the phenyl ring in the synthesized compounds towards their biological activities is evaluated.

 

CHEMISTRY

Four-step synthetic strategy yields the target molecule N-Hydroxy-3,3-dimethyl-2,6-diarylpiperidin-4-one thiosemicarbazones 28-32. A mixture of 3-methyl-butan-2-one 1, appropriate benzaldehyde 2-6 and ammonium acetate 7 in the ratio of 1:2:1, is warmed for 15 min. and hydrochloric acid was added to afford 3,3,-dimethyl-2,6-diaryl-piperidin-4-ones hydrochloride 8-12, which upon neutralization with aqueous ammonia at 0 ℃ gave the respective 3,3,-dimethyl-2,6-diaryl-piperidin-4-ones 13-17. Cyclic ketones normally undergo Baeyer-Villeger oxidation (oxygen insertion reaction) to yield lactones upon treatment with peracids.26,27 But, when 3,3-dimethyl-2,6-diaryl-piperidin-4-ones are subjected to Baeyer-Villeger type of reaction by using m-chloroperbenzoic acid, N-hydroxy-3,3-dimethylpiperidin-4-ones 23-27 resulted instead of lactones 18-22. Compounds 23-27 are converted into their thiosemicarbazones 28-32 using thiosemicarbazide in refluxing ethanol. The importance of the title compounds is due to their diverse potential, broadspectrum biological activity. The schematic representation and the analytical data of compounds 23-32 are given in Scheme 1 and Table 1, respectively. In addition, compared to 3-alkyl-2,6-diarylpiperidin-4-ones,28 all coupling constant values extracted for newly synthesized compounds 23-32 have no appreciable change, since the electro negativity of C=NNHCSNH2group is less than that of C=O. Hence it is concluded that they all exist in chair conformation only (Fig.. 1 and Fig. 2).

To grasp structure activity relationship well, numberings of the target compound are done (Fig. 3).

Scheme 1.Synthetic scheme for N-Hydroxy-3,3-dimethyl-2,6-diarylperidin-4-one thiosemicarbazones.

Table 1.Analytical data of compounds 23-32

Fig. 1.Preferred chair conformation.

Fig. 2.Preferred chair conformation.

Fig. 3.Numberings of the target compound.

 

RESULTS AND DISCUSSION

Structure activity relationship results.

Antibacterial activity

Novel N-Hydroxy-3,3-dimethyl-2,6-diarylpiperidin-4-one thiosemicarbazones 28-32 were tested for their antibacterial activity in vitro (Table 2) against Staphylococcus aureus, β-Heamolytic streptococcus, Vibreo cholerae, Salmonella typhii, Shigella felxneri, Escherichia coli, Klebsiella pneumonia and Pseudomonas. Ciprofloxacin was used as standard drug; whose zone of inhibition (mm) values for Staphylococcus aureus, β-Heamolytic streptococcus, Vibreo cholerae, Salmonella typhii, Shigella felxneri, Escherichia coli, Klebsiella pneumonia and Pseudomonas are 25, 28, 23, 22, 23, 24, 26 and 23 respectively. All the synthesized novel N-Hydroxy-3,3-dimethyl-2,6-diarylpiperidin-4-one thiosemicarbazones 28-32 exerted a wide range of modest antibacterial activity in vitro against the tested organisms. But their activity decreased upon dilution. All the compounds 28-32 are active against all the tested bacterial strains. Generally compounds containing electron withdrawing functional groups (-Cl, -F) exhibited more potent than the electron donating functional groups (-CH3, -OCH3) present on the aryl rings attached to piperidones.24 Of all the compounds synthesized, compound 31, which contains electron withdrawing chloro functional group on the para position of the two phenyl rings of the respective thiosemicarbazone, exerted a wide range of antibacterial activities against the entire tested gram-positive and gram-negative bacterial strains except Escherichia coli, besides compound 32, which contains electron withdrawing fluoride moiety on the para position of the two phenyl rings of the N-Hydroxy-3,3-dimethyl-2,6-bis(p-fluorophenyl) piperidin-4-one thiosemicarbazone which is more active against Staphylococcus aureus, grampositive cocci.

Antifungal activity

The in vitro antifungal activity (Table 2) of the synthesized novel heterocyclic compounds, 28-32 was studied against the fungal strains viz., Aspergillus flavus, Mucor, Rhizopus and Microsporum gypsuem. Fluconazole was used as a standard drug whose zone of inhibition (mm) values for Aspergillus flavus, Mucor, Rhizopus and Microsporum gypsuem are 20 ± 0.5 zone of inhibition (mm) against all the tested fungi. In general, all the synthesized compounds exerted a wide range of modest in vitro antifungal activity against all the tested organisms. But their activity decreased upon dilution. Compound 31 exerted strong antifungal activities against Aspergillus flavus, Mucor and Microsporum gypsuem. In addition, compound 32 is more potent against Microsporum gypsuem. The strong antifungal activity of compounds 31 and 32 is due to the presence of electron withdrawing functional groups like fluoro and chloro moieties attached to the aryl rings than the other compounds 28-30, which contain electron donating CH3, OCH3 groups attached to the para position of the aryl rings.

Table 2.(-)=inactive, (+)=weakly active (12-16 mm), (+)(+)=moderately active (17-21 mm), (+)(+)(+)=strong active (22-29), (+)(+)(+)(+)= highly active (30-33).

 

CONCLUSION

A close examination of the in vitro antibacterial and antifungal activity profile in differently substituted novel N-Hydroxy-3,3-dimethyl-2,6-diarylpiperidin-4-one thiosemicarbazones 28-32 against the tested bacterial strains viz. Staphylococcus aureus, β-Heamolytic streptococcus, Vibreo cholerae, Salmonella typhii, Escherichia coli, Klebsiella pneumonia, Pseudomonas and the fungal strains viz., Aspergillus flavus, Aspergillus fumigatus, Mucor, Candida albicans and Rhizopus respectively, provides a better structure activity relationship correlate, which may be summarized as follows:

Results of this study show that the nature of substituent on the phenyl ring viz., chloro as well as the fluoro functions at the para positions of the aryl moieties are determinant for the nature and extent of the anti-bacterial and anti-fungal activities of the synthesized compounds, which might have influences on their inhibiting mechanism of actions. Further development of this group of N-Hydroxy-3,3-dimethyl-2,6-diarylpiperidin-4-one thiosemicarbazones may lead to compounds with better pharmacological profile than standard drugs and serve as templates for the construction of better drugs to come to blows bacterial and fungal infections.

 

EXPERIMENTAL

Microbiology

Materials

All the bacterial strains namely Staphylococcus aureus, β-Heamolytic streptococcus, Vibreo cholerae, Salmonella typhii, Shigella felxneri, Escherichia coli, Klebsiella pneumonia, Pseudomonas and fungal strains namely Aspergillus flavus, Mucor, Rhizopus and Microsporum gypsuem are get hold of from Faculty of Medicine, Annamalai University, Annamalainagar-608 002, Tamil Nadu, India.

In vitro antibacterial and antifungal activity

The in vitro activities of the compounds were tested in Sabourauds dextrose broth (SDB) (Himedia, Mumbai) for fungi and nutrient broth (NB) (Hi-media, Mumbai) for bacteria by the Disc Diffusion method.29 The respective hydrochlorides of the test compounds 28-32 were dissolved in water to obtain 1 mg ml-1 stock solution and the different concentrations (100, 200, 500 ppm) are prepared from the stock solution. Seeded broth (broth containing microbial spores) was prepared in NB from 24 h old bacterial cultures on nutrient agar (Himedia, Mumbai) at 37±1 ℃ while fungal spores from 1 to 7 days old Sabourauds agar (Hi-media, Mumbai) slant cultures were suspended in SDB. Sterile paper disc of 5 mm diameter is saturated with the three different concentrations and such discs are placed in each seeded agar plates. The petri plates are incubated in BOD incubator at 37 ℃ for bacteria and at 28 ℃ for fungi. The zone of inhibition is recorded by visual observations after 24 hrs of inhibition for bacteria and after 72-96 hrs of inhibition for fungi. Moreover, the zone of inhibition is measured by excluding the diameter of the paper disc. Ciprofloxacin was used as standards for bacteria and fluconazole as standard for fungi under analogous conditions.

Chemistry

Performing TLC assessed the reactions and the purity of the products. All the reported melting points were taken in open capillaries and were uncorrected. IR spectra were recorded in KBr (pellet forms) on a Nicolet-Avatar–360 FT-IR spectrophotometer and note worthy absorption values (cm-1) alone are listed. 1H and 13C NMR spectra were recorded at 400 MHz and 100 MHz respectively on Bruker AMX 400 NMR spectrometer using CDCl3 as solvent. The ESI +ve MS spectra were recorded on a Bruker Daltonics LC-MS spectrometer. Satisfactory microanalysis was obtained on Carlo Erba 1106 CHN analyzer.

By adopting the literature precedent,30 3,3-dimethyl-2,6-diarylpiperidin-4-ones were prepared 13-17 were prepared.

Experimental method for the synthesis of N-Hydroxy-3,3-dimethyl-2,6-diphenylpiperidin-4-one 23: A solution of 3,3-dimethyl2,6-diphenylpiperidin-4-one 13 (0.01 mol) and m-chloroperbenzoic acid (0.01 mol) in 50 mL of chloroform was stirred for 1 hr and kept aside for overnight at 20 ℃. Then the mixture was extracted with chloroform and washed with 10% sodium bicarbonate solution. The chloroform layer was dried over anhydrous magnesium sulphate and distilled off under reduced pressure. Purifications with silica gel column chromatography with ethyl acetate: petroleum ether (bp60-80) 2:8 mixture yielded the product N-Hydroxy-3,3-dimethyl-2,6-diphenylpiperidin-4-one 23. IR (KBr) (cm-1): 3485, 3031, 2985, 2938, 1710, 723, 702; 1H NMR (δ ppm): 0.93 (s, 3H, CH3 at C-3), 1.23 (s, 3H, CH3 at C-3), 3.09 (t, 1H, H5a); 2.52 (dd, 1H, H5e, J5a,6e=14.6; J5e,6a=3.8 Hz), 3.77 (d, 1H, H2a), 3.96 (dd, 1H, H6a, J5a,5e =13.2 Hz), 4.48 (s, 1H, H1), 7.28-7.49 (m, 10H, Harom); 13C NMR (δ ppm): 21.3 CH3 at C-3, 45.4 C-5, 49.6 C-3, 70.9 C-6, 78.7 C-2, 126.8-130.2 -Carom, 137.7, 142.0 ipso-C, 210.1 C-4.

The compounds 24-27 were synthesized similarly.

N-Hydroxy-3,3-dimethyl-2,6-bis(p-methylphenyl)-piperidin-4-one 24: IR (KBr) (cm-1): 3477, 3030, 2985, 2921, 1710, 817; 1H NMR (δ ppm): 0.92 (s, 3H, CH3 at C-3), 1.24 (s, 3H, CH3 at C-3), 2.35 (s, 6H, CH3 at phenyl rings), 2.53 (t, 1H, H5a); 3.15 (dd, 1H, H5e, J5a,6e=14.6; J5e,6a=3.7 Hz), 3.76 (d, 1H, H2a), 3.96 (dd, 1H, H6a, J5a,5e=13.2 Hz), 4.75 (s, 1H, H1), 7.19-7.40 (m, 8H, Harom); 13C NMR (δ ppm): 21.0 CH3 at phenyl rings, 21.3 CH3 at C-3, 45.5 C-5, 49.7 C-3, 70.6 C-6, 78.5 C-2, 126.7-129.4 -Carom, 134.7, 137.1, 137.3, 139.1 ipso-C, 210.4 C-4.

N-Hydroxy-3,3-dimethyl-2,6-bis(p-methoxyphenyl) piperidin-4-one 25: IR (KBr) (cm-1): 3488, 3035, 2988, 2927, 2835, 1708, 831; 1H NMR (δ ppm): 0.91 (s, 3H, CH3 at C-3), 1.22 (s, 3H, CH3 at C-3), 3.07 (t, 1H, H5a); 2.50 (dd, 1H, H5e, J5a,6e=14.6; J5e,6a=3.4 Hz), 3.71 (d, 1H, H2a), 3.80 (s, 6H, OCH3 at phenyl rings), 3.91 (dd, 1H, H6a, J5a,5e=13.1 Hz), 4.60 (s, 1H, H1), 6.90-7.41 (m, 8H, Harom); 13C NMR (δ ppm): 21.3 CH3 at C-3, 45.5 C-5, 49.8 C-3, 55.1, 55.2 OCH3 at phenyl rings, 70.3 C-6, 78.2 C-2, 114.0-129.8 -Carom, 131.2, 134.1, 158.8, 159.0 ipso-C, 210.5 C-4.

N-Hydroxy-3,3-dimethyl-2,6-bis(p-chlorophenyl)-piperidin-4-one 26: IR (KBr) (cm-1): 3474, 3030, 2984, 2946, 2926, 1711, 831; 1H NMR (δ ppm): 0.92 (s, 3H, CH3 at C-3), 1.20 (s, 3H, CH3 at C-3), 3.05 (t, 1H, H5a); 2.50 (dd, 1H, H5e, J5a,6e=14.7; J5e,6a=3.8 Hz), 3.75 (d, 1H, H2a), 3.94 (dd, 1H, H6a, J5a,5e=13.2 Hz), 4.49 (s, 1H, H1), 7.26-7.48 (m, 8H, Harom); 13C NMR (δ ppm): 21.2 CH3 at C-3, 45.1 C-5, 49.6 C-3, 70.4 C-6, 78.2 C-2, 128.2-129.0 -Carom, 131.6, 133.6, 135.8, 139.9 ipso-C, 209.1 C-4.

N-Hydroxy-3,3-dimethyl-2,6-bis(p-fluorophenyl)-piperidin-4-one 27: IR (KBr) (cm-1): 3472, 3029, 2981, 2944, 2928, 1120, 1710, 829; 1H NMR (δ ppm): 0.91 (s, 3H, CH3 at C-3), 1.18 (s, 3H, CH3 at C-3), 3.02 (t, 1H, H5a); 2.49 (dd, 1H, H5e, J5a,6e=14.7; J5e,6a=3.8 Hz), 3.73 (d, 1H, H2a), 3.92 (dd, 1H, H6a, J5a,5e =13.1 Hz), 4.47 (s, 1H, H1), 7.24-7.42 (m, 8H, Harom); 13C NMR (δ ppm): 21.0 CH3 at C-3, 45.2 -5, 49.4 C-3, 70.1 C-6, 78.0 C-2, 127.2-128.8 Carom, 131.4, 133.3, 135.2, 139.4 ipso-C, 208.1 C-4.

Experimental method for the synthesis of NHydroxy-3,3-dimethyl-2,6-diphenylpiperidin-4-one thiosemicarbazone 28: A mixture of N-Hydroxy-3,3-dimethyl-2,6-diarylpiperidin-4-one 23 (0.01 mol) and thiosemicarbazide (0.01 mol) in ethanol (40 mL) was refluxed on a steam bath for 40 min and was concentrated to one-third of its original volume. After cooling, the mixture was poured over crushed ice. The solid product thus obtained was filtered off and the solid was subjected to column chromatography using ethyl acetate: petroleum ether (60:80) 2:8 as eluent to give 3,3-dimethyl-2,6-diphenylpiperidin-4-one thiosemicarbazone as crystalline solid. IR (KBr) (cm-1): 3482, 3426, 3358, 3158, 3065, 3030, 2976, 2931, 2863, 1587, 1493, 1287, 1075, 733, 702; 1H NMR (δ ppm): 0.94 (s, 3H, CH3 at C-3), 1.24 (s, 3H, CH3 at C-3), 2.34 (t, 1H, H5a); 2.61 (dd, 1H, H5e, J5e,5a=14.5; J5e,6a=3.9 Hz), 3.67 (d, 1H, H2a), 3.73 (dd, 1H, H6a, J5a,6a =13.2 Hz), 4.53 (s, 1H, H1), 6.38 (s, 2H, CSNH2), 8.57 (s, 1H, HNCS), 7.26-7.50 (m, 10H, Harom); 13C NMR (δ ppm): 21.4 CH3 at C-3, 22.4 CH3 at C-3, 31.5 C-5, 45.5 C-3, 70.1 C-6, 79.5 C-2, 126.9-128.8 -Carom, 138.1, 143.5 ipso-C, 156.1 C-4, 179.6 C=S.

The compounds 29-32 were synthesized similarly.

N-Hydroxy-3,3-dimethyl-2,6-bis(p-methylphenyl)-piperidin-4-one thiosemicarbazone 29: IR (KBr) (cm-1): 3476, 3426, 3324, 2980, 2922, 2863, 1587, 1511, 1280, 1127, 817; 1H NMR (δ ppm): 0.95 (s, 3H, CH3 at C-3), 1.32 (s, 3H, CH3 at C-3), 2.35 (t, 1H, H5a); 2.35 (s, 6H, CH3 at phenyl rings), 2.63 (dd, 1H, H5e J5e,5a=14.5; J5e,6a=3.7 Hz), 3.91 (d, 1H, H2a), 4.08 (dd, 1H, H6a J5a,6a =13.3 Hz), 4.86 (s, 1H, H1), 5.73 (s, 2H, CSNH2), 8.72 (s, 1H, HNCS), 7.19-7.45 (m, 8H, Harom); 13C NMR (δ ppm): 21.0 CH3 at phenyl rings, 22.4 CH3 at C-3, 23.3 CH3 at C-3, 29.9 C-5, 45.5 C-3, 70.7 C-6, 78.6 C-2, 126.8-129.4 -Carom, 134.6, 137.1, 137.3, 138.9 ipso-C, 156.4 C-4, 179.6 C=S.

N-Hydroxy-3,3-dimethyl-2,6-bis(p-methoxyphenyl) piperidin-4-one thiosemicarbazone 30: IR (KBr) (cm-1): 3489, 3429, 3368, 2994, 2931, 2836, 1587, 1512, 1268, 1036, 831; 1H NMR (δ ppm): 0.99 (s, 3H, CH3 at C-3), 1.47 (s, 3H, CH3 at C-3), 2.04 (t, 1H, H5a); 2.72 (dd, 1H, H5e, J5e,5a=14.5; J5e,6a=3.7 Hz), 3.80 (s, 6H, OCH3 at phenyl rings), 4.14 (d, 1H, H2a), 4.27 (dd, 1H, H6a, J5a,6a =13.6 Hz), 4.72 (s, 1H, H1), 6.09 (s, 2H, CSNH2), 8.09 (s, 1H, HNCS), 6.90-7.58 (m, 8H, Harom); 13C NMR (δ ppm): 21.3 CH3 at C-3, 22.3 CH3 at C-3, 29.6 C-5, 45.3 C-3, 55.2 OCH3 at phenyl rings, 70.2 C-6, 78.4 C-2, 114.0, 128.2-129.4 -Carom, 133.5, 138.4 ipso-C, 156.3 C-4, 179.4 C=S.

N-Hydroxy-3,3-dimethyl-2,6-bis(p-chlorophenyl)-piperidin-4-one thiosemicarbazone 31: IR (KBr) (cm-1): 3473, 3426, 3371, 2977, 2926, 2853, 1589, 1490, 1288, 1090, 830; 1H NMR (δ ppm): 1.10 (s, 3H, CH3 at C-3), 1.34 (s, 3H, CH3 at C-3), 2.44 (t, 1H, H5a); 2.73 (dd, 1H, H5e, J5e,5a=15.0; J5e,6a=3.7 Hz), 3.93 (d, 1H, H2a), 4.18 (dd, 1H, H6a, J5a,6a =13.6 Hz), 4.94 (s, 1H, H1), 6.53 (s, 2H, CSNH2), 8.57 (s, 1H, HNCS), 7.36-7.60 (m, 8H, Harom); 13C NMR (δ ppm): 21.3 CH3 at C-3, 22.1 CH3 at C-3, 29.6 C-5, 45.0 C-3, 70.6 C-6, 78.6 C-2, 128.5-128.8 -Carom, 133.6, 138.6, 141.9 ipso-C, 156.5 C-4, 179.5 C=S.

N-Hydroxy-3,3-dimethyl-2,6-bis(p-fluorophenyl)-piperidin-4-one thiosemicarbazone 32: IR (KBr) (cm-1): 3470, 3423, 3370, 2974, 2924, 2851, 1591, 1491, 1280, 1089, 830; 1H NMR (δ ppm): 1.09 (s, 3H, CH3 at C-3), 1.31 (s, 3H, CH3 at C-3), 2.41 (t, 1H, H5a); 2.71 (dd, 1H, H5e, J5e,5a=15.1; J5e,6a=3.6 Hz), 3.90 (d, 1H, H2a), 4.15 (dd, 1H, H6a, J5a,6a =13.6 Hz), 4.97 (s, 1H, H1), 6.49 (s, 2H, CSNH2), 8.52 (s, 1H, HNCS), 7.31-7.55 (m, 8H, Harom); 13C NMR (δ ppm): 21.0 CH3 at C-3, 21.9 CH3 at C-3, 29.8 C-5, 45.5 C-3, 70.4 C-6, 78.4 C-2, 128.9-129.8 -Carom, 133.4, 138.3, 141.5 ipso-C, 156.2 C-4, 179.1 C=S.

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