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Review Article Mannich Bases: an Important Pharmacophore in Present Scenario Hindawi Publishing Corporation International Journal of Medicinal Chemistry Volume 2014, Article ID 191072, 15 pages http://dx.doi.org/10.1155/2014/191072 Review Article Mannich Bases: An Important Pharmacophore in Present Scenario Suman Bala, Neha Sharma, Anu Kajal, Sunil Kamboj, and Vipin Saini M. M. College of Pharmacy, Maharishi Markandeshwar University, Mullana, Ambala, Haryana 133207, India Correspondence should be addressed to Suman Bala; [email protected] Received 8 August 2014; Accepted 8 October 2014; Published 12 November 2014 Academic Editor: Patrick Bednarski Copyright © 2014 Suman Bala et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mannich bases are the end products of Mannich reaction and are known as beta-amino ketone carrying compounds. Mannich reaction is a carbon-carbon bond forming nucleophilic addition reaction and is a key step in synthesis of a wide variety of natural products, pharmaceuticals, and so forth. Mannich reaction is important for the construction of nitrogen containing compounds. There is a number of aminoalkyl chain bearing Mannich bases like fluoxetine, atropine, ethacrynic acid, trihexyphenidyl, andso forth with high curative value. The literature studies enlighten the fact that Mannich bases are very reactive and recognized to possess potent diverse activities like anti-inflammatory, anticancer, antifilarial, antibacterial, antifungal, anticonvulsant, anthelmintic, antitubercular, analgesic, anti-HIV, antimalarial, antipsychotic, antiviral activities and so forth. The biological activity of Mannich basesismainlyattributedto, -unsaturated ketone which can be generated by deamination of hydrogen atom of the amine group. 1. Introduction [16], antitubercular [17, 18], analgesic [19], anti-HIV [17], antimalarial [20], antipsychotic [21], antiviral [22]activities Mannich bases, beta-amino ketones carrying compounds, and so forth. Along with biological activities Mannich bases aretheendproductsofMannichreaction[1, 2]. Mannich are also known for their uses in detergent additives [23], reaction is a nucleophilic addition reaction which involves resins, polymers, surface active agents [24], and so forth. the condensation of a compound with active hydrogen(s) Prodrugs of Mannich bases of various active compounds have with an amine (primary or secondary) and formaldehyde been prepared to overcome the limitations [25]. Mannich (any aldehyde) [3]. The schematic representation of general bases (optically pure chiral) of 2-naphthol are employed Mannich reaction is given in Scheme 1. for catalysis (ligand accelerated and metal mediated) of the Mannich bases also act as important pharmacophores or enantioselective carbon-carbon bond formation. Mannich bioactive leads which are further used for synthesis of various bases and their derivatives are intermediates for the synthesis potential agents of high medicinal value which possess of bioactive molecules [26, 27]. Mannich reaction is widely aminoalkyl chain. The examples of clinically useful Mannich used for the construction of nitrogen containing compounds baseswhichconsistofaminoalkylchainarecocaine,fluoxe- [28]. Mannich bases have gained importance due to their tine, atropine, ethacrynic acid, trihexyphenidyl, procyclidine, application in antibacterial activity [29]andotherapplica- ranitidine, biperiden [4–6],andsoforth.Mannichbasesare tions are in agrochemicals such as plant growth regulators. known to play a vital role in the development of synthetic pharmaceutical chemistry. The literature studies revealed 2. Biological Activities that Mannich bases are very reactive and can be easily converted to other compounds, for example, reduced to form 2.1. Antimicrobial Activity. A novel series of Mannich physiologically active amino alcohols [7]. Mannich bases are bases of 3-substituted-4-(5-nitro-2-furfurylidene) amino-5- known to possess potent activities like anti-inflammatory mercapto-1,2,4-triazoles 1(a–n) (Figure 1) was synthesized [8, 9], anticancer [10, 11], antifilarial [8], antibacterial [12, andscreenedfortheantifungalactivityagainstC. albicans 13], antifungal [13, 14], anticonvulsant [15], anthelmintic by employing disc diffusion method using nitrofurazone and 2 International Journal of Medicinal Chemistry O H O O R R NH R + 2 + R R H NR2 Nonenolizable aldehyde Primary or secondary amine Enolizable ketone Mannich base Scheme 1 R 2 R R N 1 1 2 N N R1 c H 3-Cl, 4-F-aniline d Me Morpholine R S N f Me 3-Cl, 4-F-aniline O NO2 h Et Morpholine N j Et 3-Cl, 4-F-aniline n Ph 3-Cl, 4-F-aniline 1 Figure 1 fluconazole as standard drugs for comparison. The results antibacterial activity against P. ae r ug ino s a , S. marcescens, S. revealed that all the compounds were found to be least active aureus,andE. coli [32]. as compared to nitrofurazone whereas compounds 1c, 1d, 1f, All the synthesized compounds have shown good 1h, 1j,and1n were found to have better antifungal activity antibacterial activity against P. ae r ug ino s a whereas they were as compared to fluconazole. Compound 1f substituted with found to be less potent against S. marcescens, S. aureus, methyl and chloro group has shown highest antifungal and E. coli when compared with standard drug tetracycline. activity with 17 mm zone of inhibition which is higher than Compounds 3b, 3c, and 3e substituted with nitro group zone of inhibition of fluconazole, that is, 12 mm. These results were found to be highly active among all the synthesized enlighten the key role of chloro group towards antifungal compounds [32]. activity [30]. A new series of benzamide substituted Mannich bases Mannich bases of 2-(phenyl)-2-(morpholine-4-yl)-N- 4(a–g) (Figure 4) were synthesized and evaluated for antibac- phenylacetamide 2(a–g) were synthesized (Figure 2)and terial activity against E. coli, P. aeruginosa, E. faecalis,and screened for antimicrobial activity against various bacte- S. aureus. Test tube dilution method was employed for rial and fungal strains. Ciprofloxacin and clotrimazole evaluation by using amoxicillin and cefixime as standard were used as standard drugs for antibacterial and anti- drugs for comparison. The results were recorded in terms of fungal activities, respectively. From the synthesized com- minimum inhibitory concentration (MIC). The compounds pounds, 2c, 3-(4-chlorophenyl)-3-(morpholin-4-yl)-N-phe- 4e, 4f,and4g were found to be highly active among all nylpropanamide, has shown highest antibacterial activity the synthesized compounds with comparable MIC values against S. epidermidis with 20 mm of zone of inhibition as of both standard drugs amoxicillin (1.56, 1.56, 3.125, and compared to ciprofloxacin with 15 mm. Compounds 2e,3- 3.125) and cefixime (6.25, 6.25, 12.5, and 6.25). The compound (morpholin-4-yl)-3-(4-nitrophenyl)-N-phenylpropanamide, 4g was found to be most active with MIC (3.125, 3.125, and 2f, 3-(4-methoxyphenyl)-3-(morpholin-4-yl)-N-phe- 3.125, and 6.25). These results ensured that substitutions with nylpropanamide, were found to have equipotent antibacterial sulphonamido (4e), p-nitro (4f), and dinitro (4g)groups activity as compared to ciprofloxacin against K. pneumonia enhance the antibacterial activity [33]. and nonhemolytic streptococcus,respectively.Thecom- A novel series of Mannich bases 5(a–e) (Figure 5)of pounds 2d and 2e were found to have equipotent antifungal quinoline derivative (cinchophen) was carried out and activity against M. audouinii and C. albicans as compared to screened for the antimicrobial activity against various bac- clotrimazole. The compound 2c having 4-chlorophenyl has terial and fungal strains. Norfloxacin and fluconazole were not contributed to antifungal activity [31]. used as standard drugs for antibacterial and antifungal A series of novel Mannich bases of 3-(4,6-disubstituted-2- activities, respectively. From the synthesized compounds, thiomethylpyrimidyl)-4-amino-5-mercapto-1,2-4-triazoles 5a, 5b,and5c substituted with morpholine, piperidine, and 3(a–f) (Figure 3) was synthesized and further subjected to dicyclohexylamine, respectively, have emerged out as more International Journal of Medicinal Chemistry 3 O O 2 R N N b H c Cl d OH O e NO2 O N R O N f OMe H H g N(Me)2 2a 2b–g Figure 2 R N N 3 R R1 R2 N N R N S CH2 1 Me H p-Chlorophenyl N a N CH Me H p-Nitrophenyl S 3 b Me 2-Nitro-4,5-dimethoxyphenyl N c H d Me Me p-Chlorophenyl e Me Me p-Nitrophenyl f Me Me 2-Nitro-4,5-dimethoxyphenyl 3 R2 Figure 3 O 4 R –NH SO NH C NH CH2 R f 2 2 g –NH O2N h –NH NO2 4 O2N Figure 4 CONHR 5 R H2 N a C O H2 C N N b H 2 C6H11 C N c C6H11 5 Figure 5 4 International Journal of Medicinal Chemistry 6 R N O a H H b Me R C N C H c OMe d Cl CN 6 e Figure 6 R Cl 7 RX O a H CH2 N b 4-Me CH2 c 4-OMe CH2 d 4-Cl CH2 N N X e 4-Br CH2 N O NH 4-NO CH N O f 2 2 g H O O h H N-Me 7 Figure 7 potent antimicrobial agents than cinchophen and both of screened for antibacterial activity and 4-amino-N-carba- the standard drugs. The compounds 5d and 5e were almost mimidoyl benzene sulphonamide was used as reference equipotent to cinchophen but did not respond to fungal drug. From the antibacterial screening it was found that the strains [34]. compound bearing chloro group at 5-position has prominent A series of various substituted N-[(1-piperidinoben- activity against all the bacterial strains with lowest MIC values zyl)benzamide] (PBB) 6(a–e) (Figure 6)havebeensynthe- [37]. sized. The antimicrobial activity of synthesized PBB was A series of 4-[1H-benzimidazole-yl(substituted benzal) carried out on the microorganisms S. aureus, B. subtilis, methyl-amino] benzoic acids 9(a–c) (Figure 9)wassyn- E.
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