J. Chem. Sci. Vol. 125, No. 3, May 2013, pp. 467–482. c Indian Academy of Sciences.

Mannich reaction: A versatile and convenient approach to bioactive skeletons

SELVA GANESAN SUBRAMANIAPILLAI School of Chemical and Biotechnology, SASTRA University, Thanjavur-613 401, India e-mail: [email protected]

MS received 27 December 2011; revised 17 September 2012; accepted 6 December 2012

Abstract. This review gives an insight into the recent applications of and its variants in the construction of bioactive molecules. Emphasis is given to the Mannich reaction that provides bioactive molecules and/or modifies the property of an existing bioactive molecule. The role of Mannich reaction in the construction of antimalarial, antitumour, antimicrobial, antitubercular, antiinflammatory and anticonvulsant molecules and also the significance of aminoalkyl Mannich side chain on the biological property of molecules is discussed here. Keywords. Mannich reaction; Mannich bases; bioactive molecules; antimalarial; antitumour; antitubercular.

1. Introduction O O R1 3 4 H R2 The development of new drugs and target specific 1 R R R N CH2O R2 R3 delivery agents with enhanced efficacy is essential to H N counter the multi-drug resistant (MDR) tumours 1a,b R1, R2 = or aryl R4 1 3 4 and microbial strains. The modification of an existing R , R = cyclic or acyclic β–Aminocarbonyl derivative drug molecules offers a cost and time effective conve- nient strategy to achieve new bioactive skeletons. Man- Scheme 1. Mannich reaction. nich reaction provides a suitable method to introduce aminoalkyl substituent into a molecule. 1c In several of β-aminocarbonyl compounds 1 by Mannich reaction instances, the Mannich derivatives exhibit better acti- (scheme 1). vity than the corresponding parent analogues vide infra. However, the classical Mannich reaction has limi- Moreover, the presence of Mannich side chain increases tations such as lack of selectivity, competitive aldol the solubility and hence the bioavailability of the drug reactions, etc. To overcome these limitations, modern molecule. This review surveys on the recent applica- variants of Mannich reaction utilize preformed , tions of multifaceted Mannich reaction in the synthesis enolates, appropriate use of catalyst and reaction con- of antimalarial, antitumour, antimicrobial, antitubercu- ditions, etc. 3a–j,5a–f Several chiral auxiliaries and chi- lar, antiinflammatory and anticonvulsant molecules. ral catalysts are often employed to carry out asymmet- ric Mannich-type reaction. 3b,6a–e Apart from this, basic nanocrystalline magnesium oxide, 7a recyclable copper 1.1 Mannich reaction and its modern variants nanoparticles, 7b poly(amidoamine) catalysed reac- tions 7c and microwave-assisted Mannich reactions 7d Mannich reaction 2 is one of the most fundamental and have also been reported recently. Hayashi et al. dis- important, C–C bond forming reactions in organic syn- covered high pressure asymmetric Mannich-type reac- thesis. Mannich reaction withstands a large diversity tion in frozen water medium. 7e Cimarelli et al. reported of functional groups and hence it has been witnessing three component Mannich reaction under neat condition a continuous growth in the field of organic chem- for the synthesis of diaminoalkylnaphthols. 7f istry. The surge of literature on Mannich reaction pro- vides an outstanding evidence for the diversity and applications of the reaction. 3a–j The Mannich reaction 1.1a Proline/organocatalysed asymmetric Mannich- and its variants offer a robust method for the prepa- type reaction: The proline/organocatalysed asymmet- ration of the aminocarbonyl and several other deriva- ric Mannich-type reaction plays a seminal role in enan- tives. 4a–e The following scheme depicts the synthesis tioselective and diastereoselective C–C bond forming 467 468 Selva Ganesan Subramaniapillai

NH2 OMe et al. O (S)-proline O Through quantum mechanical calculations, Fu (10 mol%) explained the origin of stereoselectivity in amino acid N CH2O H R1 R2 RT, DMSO R1 R2 catalysed direct syn and anti selective Mannich reac- 16-17 h 11 OMe Yield = up to 94% tions. Excellent reviews are available which provides ee = >99% significant insight into the proline/organocatalysed asymmetric Mannich-type reaction. 12a–e Scheme 2. Proline catalysed enantioselective Mannich reaction.

2. Applications of Mannich reaction in bioactive reactions. Herein, we present a representative example molecule synthesis of proline catalysed highly enantioselective Mannich reaction of (scheme 2). 8 The Mannich reaction and its variants are often Similarly, proline and its derivatives catalyses; mul- employed to access diverse molecules, whose ticomponent synthesis of 3-amino alkylated by applications are ranging from bioactive skeletons Mannich-type reaction, 9a Mannich reaction of acetalde- to material science. A representative list of the hyde, 9b preparation of azole Mannich adducts, 9c three bioactive/therapeutic molecules obtained by Mannich component domino reactions, 9d enantioselective addi- reaction and the role of Mannich reaction in total tion of ketones to chalkogenazines, 9e synthesis of [1,4]- synthesis are presented in chart 1. The aminocarbonyl thiazines, 9f asymmetric Mannich reaction of cyclic Mannich products are useful in the construction of ketones, 9g etc. In addition to this, various organocatal- β-peptides and β-lactams, which are present in several ysed Mannich reactions have also been reported. 10a–g bioactive molecules such as taxol (antitumour agent),

OMe O Et HO OH OH N OH Me N N N O NMe2 H N H 4 OH 2 3 5 Osnervan Moban Mulundocandin Mannich analogue (Analgesic) (Antiparkinsonic) (Neuroleptic) (Antifungal activity with increased (Ref 5a) (Ref 5a) (Ref 5a) aqueous solubility) (Ref 15)

AcOH N N N 1 aq. (CH3)2NH R1 R R1 N 6 N H C N formalin, RT H3C 3 H3C CH3 Zolpidem N O (hypnotic drug) 1 CH3 (Ref 16) R = 4-MeC6H4 N CH H C 3 H C 3 3 O N CH3 CH3 O OH Amine N Fe NH N R2 H C N S O 3 8 9 N 7 Isothiazolopyridine Mannich bases Ferrocenic aminohydroxy- Quinoline (2-10 times potent than acetylsalicylic acid) naphthoquinones (vasorelaxing property) (Ref 20) (antimicrobial activity) (Ref 18) (Ref 21) O O Me OH Me O Me N Me N H Me N

O Me CO Me Me 2 CO2Me 11 12 10 Aza-cyclo-octane Epoxy-hexahydrofuroazocine Bicyclic lactam (-like derivative) (alkaloid-like derivative) (precursor of pumiliotoxin 251D) (Ref 22) (Ref 22) (Ref 23) TBSO OTBS MeO 10 mol% L-proline O O O CHO propanal, NH O CHO NMP, -20 oC Me NHBz Me 13 NH2 N-Terminal aminoacid equivalent of nikkomycin (Ref 24)

Chart 1. Bioactive Mannich derivatives. Bioactive skeletons via Mannich reaction 469

R CH O HO O Ph 2 HO O Ph 1o or 2o amine

MeO 2-propanol, reflux MeO OH O 14 1-2 h OH O Oroxylin-A 15 R = pyrrolidinyl, piperidinyl, n-butylamino, methyl benzylamino, diphenylamino N-methyl furfuryl amino, morpholinyl, N-methylpiperzinyl, benzylamino, 1-Boc piperzinyl

Scheme 3. Mannich reaction of oroxylin-A. bestatine (immunological response modifier) and activity against Toxoplasma gondii and atovaquone SCH48461 (anti-cholesterol agent). 13a–d Tramadol 2, resistant strain of T. gondii. osnervan 3 and moban 4 are bioactive β-aminocarbonyl Mannich reaction also plays a significant role in derivatives with analgesic, antiparkinson and neurolep- bioactive skeleton target synthesis. Chernov et al. tic properties (chart 1). 5a It is believed that the solubil- reported the synthesis of alkaloid-like molecules 10 ity of the Mannich derivatives increases in water due and 11 from lambertianic acid via Mannich-type intra- to protonation of basic amine nitrogen atom. 14 Mulun- molecular ring closure reaction (chart 1). 22 Martin et al. docandin, a class of lipopeptides, showed excellent in employed vinylogous Mannich reaction to synthesize vitro activity against Candida species. However, poor bicyclic lactam 12,akeyintermediateusedinthetotal solubility restricts its widespread application. Lal et al. synthesis of alkaloid pumiliotoxin 251D (chart 1). 23 carried out a semi-synthetic modification of mulundo- Proline catalysed asymmetric Mannich reaction played candin by Mannich reaction. 15 The Mannich derivatives a vital role in the synthesis of N-terminal amino acid of mulundocandin 5 exhibited significant improvement equivalent moiety 13 of peptide , nikkomycin in solubility, while retaining the activity (chart 1). (chart 1). 24 Babu et al. synthesized biologically signifi- Mannich reaction was useful for the preparation of cant 8-aminoalkylated derivatives of oroxylin-A 15,by zolpidem 6, a hypnotic drug used for the treatment of Mannich reaction. 25 The α-glucosidase inhibitory insomnia (chart 1). 16 The Mannich bases are obtained activity of the aminoalkyl derivatives was found to be by the condensation reaction of C–H acidic substrates superior to that of their parent molecule oroxylin-A 14 (ketones, phenols, etc.,), amine (cyclic or acyclic) and (scheme 3). . The Mannich bases are an important class of molecules with significant biological activity. The cationic surfactant molecules obtained from Mannich 2.1 Synthesis of antimalarial molecules bases possess excellent fungicidal property along with good biocidal property against Gram-positive Malaria is one of the most widespread infectious dis- and Gram-negative bacteria. 17 The quinoline derived eases in the world. Though effective antimalarial drug Mannich base 7 possess vasorelaxing properties like chloroquine exists, drug resistance has become (chart 1). 18 Such molecules are useful in the treatment a great challenge. The development of new inexpen- of hypertension. 1,2,4-Triazole derived Mannich bases sive antimalarial drugs is vital in developing coun- exhibited anticancer activity. 19 The isothiazolopyridine tries to counter multi-drug resistant Plasmodium fal- derived Mannich bases 8 were found to be 2 to 10 times ciparum. 26 The discovery of new molecular skeletons more potent than the reference drug acetylsalicylic is always in need to circumvent the drug resistance acid (chart 1). 20 The Mannich reaction is useful for the and to provide good antimalarial activity. In 1997, synthesis of ferrocenyl derived aminohydroxynaphtho- Kotecka et al. reported the synthesis of chloroquine quinones 9 (chart 1). 21 These products exhibited good analogues, a quinoline based di-Mannich bases (16

CH2NR2 HO CH2NR2

HN OH HN Z

Y CH2NR2 Y CH2NR2 X N 16 X N 17

X = CF3, Cl; Y = H, Me; NR2 = NEt2, pyrrolidinyl, X = Cl, CF3; Y = H, Me; Z = H, Me; NR2 = piperidinyl, piperidinyl, 2-methylpiperidinyl, 4-methylpiperazinyl pyrrolidinyl, 3-methylpiperidinyl, 3,5-dimethylpiperidinyl

Figure 1. Quinoline di-Mannich bases. 470 Selva Ganesan Subramaniapillai

H H O H O O O O O CH O, R1R2NH O O 2 O H H H H O H H O EtOH, AcOH O RT, 30 min 18 NR O NR

R = H, Me 1 2 18a 19 NR R -N-R1R2 = N , N O , N N , N N , N

N S , N N , N SO2 , N , N

Scheme 4. Mannich reaction of artemisinin C-10 analogues. and 17), and screened their activity against multi-drug used for the haemoglobin hydrolysis by the para- resistant strains of Plasmodium falciparum (figure 1). 26 site. 28 The phenolic Mannich bases possess good The ex vivo antimalarial activity of the Mannich bases biological activity partially due to the liberation of tested in serum were found to be greater than those of α,β–unsaturated ketones by deamination. The α,β– amodiaquine, chloroquine or pyronaridine. unsaturated ketones have good affinity toward thiols The widespread application of artemisinin 18,aneffi- and hence they may selectively bind and inhibit the cient antimalarial drug utilized in malaria chemother- cysteine proteases. Chipeleme et al. synthesized pheno- apy, is limited due to its poor solubility in both water lic Mannich bases 20 by treating equimolar quantities and oil. Moreover, artemisinin and its semi-synthetic of 2,4-dihydroxybenzaldehyde, and sec- analogues dihydroartemisinin, artemether, arteether, ondary amine in ethanol solvent (scheme 5). 28 The sodium artesunate are easily removed from the blood phenolic Mannich bases subsequently converted to the stream and hence lead to the resurgence of the par- corresponding (thio)semicarbazone 21 and amino- asite. 27 It is postulated that the amine functionality quinoline semicarbazone derivatives. The 4- embedded in artemisinin may enhance the drug activ- aminoquinoline semicarbazones effectively inhibit ity by accumulating in parasitic acidic food vacuole. falcipain-2, the cysteine protease present in Plasmod- Pacorel et al. reported the synthesis of artemisinin Man- ium falciparum; while bisquinoline semicarbazone nich derivatives 19, from C-10-α-pyrroleartemisinin 22 exhibited good antimalarial activity with an IC50 derivative 18a (scheme 4). 27 The presence of Mannich of 0.07 μM against chloroquine resistant strain of side chain increases its solubility and hence bioavail- Plasmodium falciparum. ability of the drug when compared to the non-basic The factors that determine the transformation of a derivatives. The morpholine and N-methylpiperazine bioactive skeleton to a drug are adsorption, distribu- derived semi-synthetic analogues were three times tion, metabolism and excretion (ADME) properties. 29 more potent than the natural product artemisinin against Hence, early prediction of ADME properties could both chloroquine sensitive and resistant strains. lead to better identification of therapeutic molecules. Malarial infections can be controlled by inhibiting Based on this, Guantai et al. reported a new antimalar- cysteine proteases, a sulfur-containing vital enzyme ial hybrid compound by replacing the triazole tether

HO R1R2NH, CH O HO 2 HO X thio/semicarbazide EtOH 2 1 R2R1N R R N N CHO CHO MeOH, reflux N NH2 65 oC, 1 h H OH OH 1 h OH 20 21 X = O or S Cl HO O H NR1R2 = NEt pyrrolidino, piperidino, N N 2, N N morpholino, methylpiperazino, N N N H H 4-(7-Cl-quinolinyl)-piperazino OH N

22 Cl

Scheme 5. Synthesis of quinoline semicarbazone. Bioactive skeletons via Mannich reaction 471 group of an existing molecule with piperazinyl moi- Hence, prolonged use of amodiaquine is restricted. ety. 29 The target molecules 25 and 26 were obtained It was hypothesized that the interchange of amine and by the Mannich reaction of piperazinyl derivative 23 hydroxyl functionality would lead to the formation of with formaldehyde and chalcone 24 in ethanol solvent new amodiaquine Mannich analogue, isoquine 29a,that (scheme 6). The compounds 25 and 26 were found resist oxidation by cytochrome P-450 enzyme. In 2003, to be the most active analogues against Plasmodium O’Neill et al. reported the synthesis of isoquine ana- falciparum. The piperazinyl tethered derivatives pos- logues by coupling chloroquinoline with phenolic Man- sess good antimalarial properties along with improved nich bases 30 (scheme 8). 30 The isoquine products solubility. 29b thus obtained exhibited good antimalarial activity; Amodiaquine 27, a 4-aminoquinoline antimalarial and hence it offers an effective and safe alternative to drug is effective for treating both chloroquine sensi- amodiaquine. tive and resistant strains of Plasmodium falciparum. Amodiaquine N-Mannich base derivatives exhibited However, enzymatic in vivo oxidation of amodi- good stability, antimalarial activity against multi-drug aquine by cytochrome P-450 could form amodiaquine resistant Plasmodium falciparum. 31 Later, Saha et al. quinoneimine (AQQI) 28; a reactive metabolite that prepared isoquine derivatives 29c and examined could lead to side effects such as agranulocytosis and their efficacy against chloroquine sensitive strains of liver damage (scheme 7). 30 Plasmodium falciparum (figure 2). 32 However, the

R HO H N O OMe N O N R CH O, EtOH 2 OMe N reflux at 110 oC , 12 h HO OMe N Cl 24 OMe 23 N Cl 25 R = H (49%), 26 R = OMe (66%)

Scheme 6. Synthesis of antimalarial hybrid compounds by Mannich reaction.

OH Et Et O Et N Et N N Et OH Et NH N P-450 [O] NH

Cl N Cl N 27 28 Cl N Amodiaquine 29a Amodiaquine quinoneimine (AQQI) (causes hepatotoxicity and Isoquine agranulocytosis) (resistance to oxidation)

Scheme 7. Oxidative disintegration of amodiaquine.

NR1R2

OH NR1R2 (1) 20% HCl/EtOH/reflux OH R1R2NH OH 6 h CH2O NH EtOH (2) 4,7-dichloroquinoline EtOH, reflux, 12 h NHCOCH3 reflux, 24 h NHCOCH3 Cl N 30 1 2 29b R , R = methyl, ethyl, n-propyl, n-butyl, (CH2)4, (CH2)2O(CH2)2, (CH2)5 R1 =H, R2 = Et or i-propyl or t-butyl

Scheme 8. Synthesis of isoquine analogues by Mannich reaction. 472 Selva Ganesan Subramaniapillai synthesized analogues were found to be inferior to the disintegration to form toxic tebuquine quinoneimine. antimalarial drug chloroquine. The nature of Mannich Miroshnikova et al. synthsized isotebuquine analogues substituent plays a significant role in determining the 34a–e by Mannich reaction and the products exhibited activity of isoquine derivatives. good antimalarial activity (scheme 9). 33b The 4-aminoquinoline derived Mannich bases 31 Interestingly, mono-Mannich base derivatives were and 32 showed good antimalarial activity (figure 3). 33a found to be more active than the di-Mannich base However, the Mannich analogues displayed higher derivatives. cytotoxicity to the mammalian cells, especially to highly drug-resistant glioblastoma cell line. Hence, these Mannich bases could be used as antiproliferative 2.2 Synthesis of antitumour molecules agents rather than antimalarial drugs. Akin to amodiaquine 27, tebuquine 33,a4- Highly drug-resistant tumour cells limit the success rate aminoquinoline antimalarial drug undergoes oxidative of the cancer chemotherapy. The use of doxorubicin, an anthracycline chemotherapeutic agent causes multi- drug resistance in tumour cells. The anthracycline 1 2 NR R synthetic analogue 4,11-dihydroxynaphtho[2,3- OH f ]-5,10-dione Mannich base 35 showed sig- nificant activity against multi-drug resistant tumour cell lines (figure 4). 34a The presence of aminoalkyl NH Mannich side chain is essential to formulate water soluble antitumour agent 36 (figure 4). 34b The gati- Cl N floxacin Mannich derivative 37 showed excellent 29c 1 2 1 2 1 2 R , R = -CH2CH2OH, i-propyl; R = Ph, R = H; R = H, R = CSNH2 anticancer activity compared to the standard anticancer drug etoposide (figure 4). 34c Mannich Figure 2. Isoquine derivatives. derivatives 38 exhibited good activity against Jurkat cell lines (figure 4). 34d The recent applications of Man- nich reaction in construction of antitumour skeleton is H N R1 HN HN N R1 presented here. R2 H Fe R2 Antimitotic agents play a significant role in treating multi-drug resistant tumours. Both tryprostatin A and B Cl N Cl N 31 32 obtained from natural source, act as antimitotic agents. 1 2 R = R = CH3 R1 = R2 = CH Yamakawa et al. employed Mannich reaction as one 1 2 3 R = Ph, R = (CH2)2N(CH3)2 R1 = Ph, R2 = (CH ) piperidine 1 2 2 2 of the synthetic pathway to prepare tryprostatin A and R = Ph, R = (CH2)2piperidine B. 34e Scheme 10 depicts the total synthesis of trypro- Figure 3. 4-Aminoquinoline Mannich bases. statin A 40a by coupling 2-prenylindole intermediate

R R OH 1 R R CH2NHC(CH3)3 OH NH

NH t-BuNH2 NH HN OH HN OH CH2O, DMF Cl N 3 days NH 33 (Tebuquine) Cl N 1 = Cl N Cl N R 4-ClC6H4 33a R = Cl, CF3 34a 34b

R R R

NH NH

NH NH HN OH HN OH HN OH NH

Cl N N Cl Cl N 34c 34d 34e

Scheme 9. Synthesis of isotebuquine analogues by Mannich reaction. Bioactive skeletons via Mannich reaction 473

N O OH N Amine SO2NH N HO O N H3CO OCH3 N N N H Br O OH O 35 36 O F 4,11-Dihydroxynaphtho[2,3-f ]indole- N O 5,10-dione Mannich bases OH Topotecan O N N O (anticancer activity) (water soluble antitumour agent) (Ref 34a) (Ref 34b) H3C H3CO N OH NR1R2 2HCl 37 NR1R2 Acetophenone Mannich bases Gatifloxacin Mannich base Cytotoxic in both (anticancer activity better than human T (Jurkat) cells and mouse standard drug etoposide) O renal carcinoma (Ref 34d) 38 (Ref 34c)

Figure 4. Antitumour Mannich derivatives.

H H O O N N CH O N NH NH 2 O O Me2NH.HCl H H R R MeO N AcOH, dioxane H MeO N R R RT 39 H MeO N MeO N H H 40a 40b R = -CH2-CH=C(CH3)2 Yield = 40% Yield = 30% tryprostatin A 9-epi-tryprostatin A

Scheme 10. Tryprostatin synthesis by Mannich reaction.

O S Ar O EtOH, reflux N Ar CH2O S N NH O N N O 18-22 h N OH 42 OH Ar = phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 4-isopropylphenyl, 4-trifluorophenyl, 4-nitrophenyl, 2-nitrophenyl, 4-t-butylphenyl, 3,4-dimethoxyphenyl, 4-trifluoromethoxyphenyl

Cl O NO2 O N S N N I N CH OH 3 41 OH 42a

Clioquinol Improved antiproliferative property

Scheme 11. Clioquinol Mannich derivatives-I.

39 with diketopiperazine core. However, the selectivity major role in determining cell proliferation and apopto- achieved in this reaction was poor. sis (cell death). The low level ROS induces cell proli- Clioquinol 41, an 8-hydroxyquinoline derivative feration, while the medium level arrest the cell growth; possesses antibiotic, anti-Alzheimer, and moderate anti- and the excess ROS causes apoptosis. 36 Chen et al. proliferative properties. Shaw et al. studied the structure- reported the synthesis of clioquinol Mannich deriva- activity relationship (SAR) of 8-hydroxyquinoline tives 43 and established that they trigger production derived Mannich bases 42 as anticancer agents of ROS and exhibit cytotoxicity (scheme 12). 36 The (scheme 11). 35 The SAR studies revealed that the derivatives are 26 times more potent than the par- presence of 8-hydroxyquinoline core was essential for ent analogue, against HeLa cell line. The studies con- the activity. The Mannich derivative 42a was found to firm the fact that the presence of Mannich side chain be active against both HeLa and BT483 cells with GI50 improves the activity of an existing bioactive molecule. values of 0.7 and 1.9 μM, respectively. The semi-synthetic lactone analogue 44 obtained The reactive oxygen species (ROS) such as hydrogen from the natural product 6α,7β-dihydroxyvouacapan- peroxide, singlet oxygen, hydroxyl radical, etc., plays a 17β-oic acid, showed better anticancer activity than 474 Selva Ganesan Subramaniapillai the corresponding parent molecule. It Benzothiazoles are an important class of molecules was proposed that the aminoalkyl Mannich deriva- with powerful antitumour activity. 39a,b The benzothia- tives could further improve the efficacy of bioac- zole derivative 46, is an orally active, potent antitumour tive molecule 44. Euzébio et al. synthesized 6α- agent, used for treating solid tumours (scheme 14). hydroxyvouacapan-7β,17β-lactone Mannich deriva- Kumbhare et al. reported zinc chloride cat- tives 45 and the products exhibited good antipro- alyzed Mannich reaction of 2-arylimidazo[2,1- liferative activity against NCI-ADR/RES, NCI-H460 b]benzothiazoles 47 (scheme 14). 40a The Mannich and K562 cancer cell lines (scheme 13). 37 The Man- base product 48a showed significant anticancer activity nich bases 45 displayed similar potency as that of against MCF-7, HeLa and HepG2 cell lines and hence, reference drug doxorubicin. Theoretical studies on it could be an effective lead for benzothiazole based Mannich bases indicated that the aminoalkyl Mannich anticancer drug molecules. side chain plays a vital role in determining antiprolife- Aminophosphonates, an interesting class of organic rative activity. compounds with antibacterial and antiproliferative/ Longshaw et al. developed Mannich reaction assisted antitumour properties. 40b–d Jin et al. employed Mannich- synthesis of sulfur-free transition state analogue type reaction to synthesize α-aminophosphonates by inhibitors of human MTAP (an anticancer target). 38 reacting substituted benzothiazole 49, dialkyl phos- phite and substituted benzaldehyde in ionic liq- 40e Y uids (scheme 15). The Mannich reaction provides Y a clean and atom economic method to access α- CH2O EtOH Z aminophosphonates 50. The ionic liquid [bmim][PF6], Z NH X N reflux X accelerated the Mannich addition reaction to several- OH 43 OH folds and the products were obtained in excellent yield. X = N, CH; Y = H, NO2; Z = CH2, NSO2Ph, NSO2C6H4(4-CH3) The benzothiazole substituted α-aminophosphonate 50a was active against PC3 cell lines. Scheme 12. Clioquinol Mannich derivatives-II. The chalcone Mannich bases exhibited good cytotox- icity against leukemia and several other human tumour cell lines. Reddy et al. stated that ‘presence of a Man- R1 N nich base group in chalcones and other compound types O O R2 may increase biological potency due to the greater H R1 H number of molecular sites for electrophilic attack by 1. THF, reflux 41 O N O cellular constituents’. The chalcone derivatives 52 O R2 2. NH4OH O were synthesized by condensing substituted acetophe- OH OH 44 45 none Mannich bases 51 with heterocyclic/aromatic R1, R2 = -CH CH , -CH CH CH , -CH CH(CH ) , -(CH ) -, -(CH ) -, -(CH ) -O-(CH ) - 2 3 2 2 3 2 3 2 2 4 2 5 2 2 2 2 (scheme 16). The chalcone derivatives 53 Scheme 13. Hydroxyvouacapan-7β,17β-lactone Mannich and 54 showed good activity against MCF-7 breast derivative synthesis. cancer cell line.

R1 R1 ZnCl2 R2N R2NH, CH2O N N N EtOH, RT N 4-5 h R S R S 48 47 1 R = H, F, CH3, OC2H5; R = H, Cl;

R2N = morpholino, pyrrolidino, 4-(2-pyridinyl)piperazino (CH2)2NEt2HCl O N

N N N N HCl F S 48a S 46 YM-201627

Scheme 14. Synthesis of benzothiazole Mannich bases. Bioactive skeletons via Mannich reaction 475

CHO R2 R1 1 S O IL R S NH H 2 P H o N 3 100-102 C 3 N 2 R3O OR N P(OR ) 49 R O 50 IL = ionic liquid

R1 = 4-Me, 6-OMe F R2 = 2-F, 4-F, 4-CF 3 S R3 = Me, Et, n-propyl, n-butyl, i-propyl H N n H C N O P(O Bu) 3 50a

Scheme 15. α-Aminophosphonate Mannich bases.

HO HO Ar HO Ar-CHO morpholine, CH O O O 2 N N o O Base O reflux, 120 C 51 52 O 18-22 h Ar = 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-, 2-, phenyl, 3-methyl-2-thiophene, 5-methyl-2-thiophene

O HO N N MeO N OH O

O 53 OH O 54

Scheme 16. Heterocyclic chalcone Mannich bases.

S H O NH N (CH2)n N S N NH Ar NH2 O O2N R R O O 55 O N N n = 1, 2, 3, 4; R = amine; Ar = aryl N (exhibit antibacterial activity) 56 N (Ref 43) R = H, NO2, Cl, Br, CH3 O 57 R2 (exhibit antibacterial activity) (Ref 45) (inhibit growth of bovine viral diarrhea virus) HN (Ref 47) N N F S R = 4-N(CH3)2, 4-Cl, 3,4-O-CH2-O- N 2 Cl R = 4-F, 3-Cl-4-F N Cl (exhibit antifungal activity) (Ref 49) 58 R

Figure 5. Representative list of antimicrobial agents.

2.3 Synthesis of antimicrobial agents cules. 42b–f Lóránd et al. studied the antibacterial pro- perties of unsaturated Mannich ketones 55 (figure 5). 43 The development of new antimicrobial agents is needed The presence of Mannich side chain increases the water to counter the increasing number of multi-drug resis- solubility of the unsaturated Mannich ketones. Hence, tant (MDR) strains. 42a The multiple mechanisms ope- the Mannich derivatives are easily transported to the rating in the bacteria makes them highly resistant to site of action and they were found to be more potent widely used antibacterial drugs and hence newer gene- than the parent molecule. Moreover, the antibacterial ration are in need to evade the drug resis- Mannich products displayed much less cytotoxicity, tance mechanism. The Mannich reaction has been which is a vital requirement for a molecule to be devel- useful in the preparation of various antimicrobial mole- oped as drug. Later, Lóránd et al. also reported that 476 Selva Ganesan Subramaniapillai the reduction of cyclic Mannich to the corre- Mazzei et al. reported the synthesis and antivi- sponding alcohol led to a significant loss in antibacterial ral studies of Mannich bases 61 and the correspond- activity. 44 ing propyl derivative of Mannich bases 62 The Mannich base derivative of isatin-4-amino-N- (scheme 18). 51 It is interesting to note here that the carbamimidoyl benzenesulphonamide Schiff’s base 56 Mannich derivative with free hydroxyl functionality 61 was found to be more active than the reference drug exhibits negligible antiviral activity against hepatitis C sulphaguanidine (figure 5). 45 The studies on 2-[(2,6- surrogate viruses. It is only the Mannich ether derivative dichlorophenyl)amino]phenylacetic acid isatin deriva- 62 that exhibits good antiviral activity. tives revealed that the presence of bulky phenyl acetic The pharmaceutically important bischromones acid moiety could reduce the antimicrobial potency of can be synthesized using Mannich reaction. 52 Bis- isatin derivatives. 46 The Mannich derivative of indole- chromones with ester or carboxylic acid functionalities 2,3-dione derivative 57 inhibit the growth of bovine act as cure for hay fever, urticaria and viral infections. viral diarrhea virus in MDBK CODA cells (figure 5). 47 The reaction of bischromone-3,3-dicarboxaldehyde Joshi et al. accomplished the synthesis of non-toxic 63, N-methylglycine and formaldehyde gave the cor- aminoalkyl substituted isonicotinyl hydrazide by Man- responding di-N-(chromone-3-ylmethyl)-N-methyl- nich reaction. 48 The Mannich products were found glycine 64 in moderated to good yields (scheme 19). to be more active against several Gram-positive and The bischromones with α-amino acid are pharmaceu- Gram-negative bacteria. Karthikeyan et al. reported tically important molecules and can also be used as the synthesis and biological activity of 2,4-dichloro-5- fluorescent marker. fluorophenyl substituted Mannich base derivatives 58 Mannich reaction offers an effective method to syn- 49 (figure 5). The Mannich base derivatives showed good thesize β-amino carbonyl derivatives. The CeCl3 cata- antibacterial and antifungal properties. lysed, microwave-assisted three-component Mannich Recently, Plech et al. reported the synthesis of tri- reaction of ketones, aromatic aldehydes and azolinothione Mannich bases 60, by reacting 1,2,4- under neat condition gave the corresponding β-amino- triazolino-3-thione 59, and formaldehyde carbonyl product 65 in excellent yield (scheme 20). 53 in ethanol solvent (scheme 17). 50 The studies revealed Most of the Mannich derivatives exhibited significant that the presence of Mannich side chain in 60 imparts antibacterial activity as compared to that of standard several-fold increase in antibacterial activity. drug, ceftriaxone. In addition to the aforementioned Mannich deriva- tives, quinazoline thione Mannich bases 66, carbox- amide derived Mannich bases 67 and acetophenone derived Mannich bases 68 also possess good anti- microbial activity (figure 6). 54–56 The Mannich deriva- N tives 68 exhibit 2 to 16 times higher antifungal activity H than the reference molecule amphotericin B. N N CH O N N S 2 S pyrrolidine N N Highly active against EtOH bacterial strains 1 h 2.3a Synthesis of antitubercular molecules: Due to Cl Cl 59 60 CH CH multi-drug resistance, Gram-negative bacteria and inactive 3 3 Mycobacterium are difficult to treat with currently Scheme 17. Triazolino-3-thione Mannich derivatives. available antibiotics. Partial/insufficient treatment is

NR2 NR CH CH CH Br 2 HO O O HO O O 3 2 2 R2NH, CH2O O O O DMF, K2CO3 EtOH 1 61 1 1 R R 62 R = H, Me inactive 1 antiviral activity R

NR2 = N O , N O N N CH3 , , N , N N COCH3 , O N(CH3)CH2COOH , N N CH CH=CH-C H 2 6 5 , N N COOEt, N N CH2

Scheme 18. Antiviral Mannich derivatives. Bioactive skeletons via Mannich reaction 477

O O H3C H

O CHO N CO2 CH2O O O H3C OH (CH2)n N MeOH O O H (CH2)n O O O CHO O N CO2 O n = 3, 4, 5 63 O H3C H 64

Scheme 19. Deformylative Mannich-type reaction of bischromones.

R2 O O HN

CeCl 1 1 2 3 R R -CHO R -NH2 microwave, 3 min 65 R1-CHO = benzaldehyde, 4-fluorobenzaldehyde, 2-chlorobenzaldehyde, 2-fluoro-5-methoxybenzaldehyde, benzofuran-2- aldehyde, pyridine-4-carboxaldehyde, 2-allyloxybenzaldehyde, 2-hydroxy-3-methylbenzaldehyde, 4- 2 ethylbenzaldehyde; R -NH2 = t-butylaniline, 2,4-difluoroaniline, 4-cyanoaniline, 3,4-difluoroaniline, 3-fluoroaniline, 3,4,5- trifluoroaniline, 3-methoxyaniline, 2-methyl-5-aminoindole, naphthylamine

Scheme 20. Antibacterial Mannich-β-amino ketone derivatives.

O NHR NR OH S 2 O OH O OH O O N S O Me N N N HCl N H H H Ar H Me OH CH2 N HO CH3 H N CH3 CH3 66 67 68

-NR2 = (CH3)2N-, (C2H5)2N-, R = sulphadiazene, sulphamethoxazol, Ar = C6H5, 4-MeC6H4, 4-MeOC6H4, sulphanilamide, sulphaguanidine, 4-ClC 6H4, 4-FC6H4, 4-BrC6H4, N O , N sulphadoxine, sulphacetamide 4-HOC6H4, 4-NO2C6H4, C4H3S(2-yl)

(Ref 54) (Ref 55) (Ref 56)

Figure 6. Antimicrobial derivatives.

OH OH H R2 N N R1 O O O OH O Amine O H N paraformaldehyde MeO OH CH3COOH 69 o O O THF, 120 C, 2 h 70 H2N Novobiocin NR1R2 = hydrophobic/polar neutral/ O acidic/basic groups

Scheme 21. Novobiocin Mannich derivatives. one of the prime reasons for the resurgence of multi- bited better activity than novobiocin against the M. drug resistant tuberculosis (MDR-TB). The presence tuberculosis. of MDR-TB has led to the development of new effec- Parthiban et al. reported the synthesis of 2,4-diaryl-3- tive and less toxic drug candidates. The isatin Mannich azabicyco[3.3.1]nonan-9-one O-methyloximes 72a and base derivative exhibits several interesting biologi- the corresponding N-methyl analogs through modified cal activity such as antiviral, antifungal, antibacterial Mannich reaction (scheme 22). 58 including antitubercular activity. 57a The structural mod- The Mannich product 72b displayed promising acti- ification of the bioactive molecule could improve its vity against Mycobacterium tuberculosis. The Mannich desirable properties. The reaction of novobiocin 69, reaction of substituted triazole, formaldehyde and amine and paraformaldehyde in the presence of acid cyclic amines in ethanol-dioxane solvent mixture catalyst yielded the corresponding Mannich deriva- gave the corresponding triazole Mannich derivative 73 tive 70 (scheme 21). 57b The Mannich products exhi- (scheme 23). 59 The mannich products thus obtained 73a 478 Selva Ganesan Subramaniapillai

O

CHO O 1 EtOH R R1 2 R2 2 3 1 CH3COONH4 N R R R H R2 71 R3 R3 1 R = H, Cl, Br, F, CH , OCH , OC H 2 EtOH CH3ONH2.HCl 3 3 2 5 R = H, Cl, Br, F, OCH3 3 reflux CH3COONa.3H2O R = H, Cl, Br, F, CH3, CH2CH3, CH(CH3)2, SCH3, OCH3, OC2H5, OC H , OC H , OCH CH=CH , OCH Ph, OCOCH 3 7 4 9 2 2 2 3 OCH N 3 OCH N 3 R1 R1 R2 R2 N H Ph N Ph R3 R3 H 72a O 72b O

Scheme 22. Antitubercular Mannich derivatives-I.

R The Mannich products 76a and 76c exhibited good CH O H 2 N N N N Cyclic secondary amine S inhibitory action against nitric oxide (NO) produc- S EtOH-dioxane N N N N tion while the products 76b and 76d displayed good N .− RT, 2-3 h S inhibition of O generation. Hence, these Mannich S N 2 73 Ar derivatives are potential lead molecules for antiinflam- Ar matory drugs. Fabio et al. employed metal triflate mediated asymmetric Mannich-type condensation reac- S S N N tion to synthesize orally bioavailable antihyperalgesic 62 N N tetrahydroquinoline derivative 77 (figure 7). N N N N N O N N S N S N O N N 73a O 73b 2.5 Synthesis of anticonvulsant molecules Scheme 23. Antitubercular Mannich derivatives-II. Anticonvulsant molecules are used to treat epilep- tic seizures, bipolar disorder and neuropathic pain. and 73b exhibited excellent antitubercular activity akin The currently available antiepileptic drugs phenytoin, to first line drug, isoniazid. mephobarbital induce side effects such as sedation and hypnosis. 63 There is ever-mounting need for new anti- 2.4 Synthesis of antiinflammatory molecules convulsant agents to control all kinds of fits, with minimal or no side effects. Recently, Obniska et al. Antiinflammatory drugs are used to treat pain and reported the synthesis and studies of Mannich bases inflammation. Ibuprofen is a well-known non-steroidal derived from [7,8- f ]benzo-2-azaspiro[4.5]decane-1, antiinflammatory drug. Prolonged use of ibuprofen 3-dione and [7,8- f ]benzo-1,3-diaza-spiro-decane-2,4- leads to ulceration and nephrotoxicity. 60a The car- dione 78 (scheme 25). 64 The Mannich reaction boxyl derivative of non-steroidal antiinflammatory drug of (di)azaspirodiones with substituted piperazine/ exhibits improved antiinflammatory properties with morpholine and formaldehyde gave the corresponding minimal side effects. 60b Sujith et al. reported the Man- Mannich bases 79 and 80 in moderate to good yields. nich reaction of ibuprofen triazole derivatives 74 with The Mannich products have better activity than the formaldehyde and secondary amine (scheme 24). 60c reference drug, phenytoin. The ibuprofen Mannich derivative 75a showed excel- The preparation of substituted urea derivatives lent antiinflammatory activity than the parent molecule. by Mannich reaction has been reported recently Moreover, the product also exhibited good analgesic (scheme 26). 65 The Mannich derivative 1-(4- effect. The analgesic effect of compound 75 was higher chlorobenzylidene)-3-(1-(morpholinomethyl)-2,3- than the reference drug, diclofenac. The condensation dioxoindolin-5-yl)urea 81 possess significant anti- of heterocyclic aldehydes with acetophenone Mannich epileptic property with the absence of neurotoxicity. bases yielded the corresponding heterocyclic chalcone Byrtus et al. synthesized Mannich derivatives Mannich derivatives 76a–d (figure 7). 61 of 5-cyclopropyl-5-phenyl-imidazolidine-2,4-dione. 66 Bioactive skeletons via Mannich reaction 479

NR2 N N N NH R2NH, CH2O CH N S CH N S 3 3 EtOH, RT, 12 h N N 75 74 Ar Ar N O N N H H H H N N N N N CH3 S R NH = , N 2 , , , (C6H5)2NH O N N N

CH3 C2H5 C6H5

75a Cl

Scheme 24. Ibuprofen Mannich analogues.

O O N N OH HO EtO O N N N O

N N O OH O 76c 76b O 76a MeO Cl N

76a-d (Ref 61) N (inhibitors of NO production and N OH O HN superoxide anion generation) O 76d O NaOOC 77 (potent anti-hyperalgesic agent) (Ref 62)

Figure 7. Antiinflammatory heterocyclic Mannich bases.

morpholine 4-substituted piperazine CH O X X 2 X CH2O O O 96% EtOH O 96% EtOH O N O N O N 12 h, RT 12 h, RT 78 H N N X = CH2; succinimide derivative 80 X = NH ; hydantoin derivative O N 79 R R = C6H5, 2-FC6H4, 4-FC6H4, 3-ClC6H4, 3-CF3C6H4, -CH2C6H5, -(CH2)2OH

Scheme 25. Anticonvulsant Mannich bases.

O O R CH2O O N O O2N 2 H N N O O N N O H HN X O N N N X X Cl H O N N X = -CH2, -O- O R = H, 4-Cl, 2-Cl, 4-F, 4-Br, 4-NO2, 3-NO2 O N 4-OH, 4-CH3, 4-OCH3 81 N O

Scheme 26. Anticonvulsant urea Mannich derivatives. 480 Selva Ganesan Subramaniapillai

However, the parent molecule exhibited better anti- 1069; (e) Ollevier T and Nadeau E 2007 Org. Biomol. convulsant activity than the corresponding Mannich Chem. 5 3126 derivatives. 5. (a) Arend M, Westermann B and Risch N 1998 Angew. Chem. Int. Ed. 37 1044; (b)Córdova A 2004 Acc. Chem. Res. 37 102; (c) Notz W, Tanaka F and Barbas III C F 2004 Acc. Chem. Res. 37 580; (d) Ruan S-T, Luo 3. Conclusions J-M, Du Y and Huang P-Q 2011 Org. Lett. 13 4938; (e) Ranieri B, Curti C, Battistini L, Sartori A, Pinna This review presents the significance of Mannich reac- L, Casiraghi G and Zanardi F 2011 J. Org. Chem. 76 10291; (f) Wang C-J, Dong X-Q, Zhang Z-H, Xue Z-Y tion and its variants in the construction of bioactive and Teng H-L 2008 J. Am. Chem. Soc. 130 8606 skeletons. The introduction of aminoalkyl Mannich 6. (a) Periasamy M, Ganesan S S and Suresh S 2010 Tetra- side chain mainly used to increase the solubili- hedron: Asymmetry 21 385; (b) De Graaff C, Ruijter E ty, bioavailability and/or activity of the existing and Orru R V A 2012 Chem. Soc. Rev. 41 3969; (c) therapeutic/bioactive molecules such as artemisinin, Periasamy M, Suresh S and Ganesan S S 2006 Tetrahe- topotecan, gatifloxacin, clioquinol, etc. Moreover, the dron: Asymmetry 17 1323; (d) Annunziata R, Benaglia M, Cinquini M, Cozzi F and Raimondi L 1993 Tetra- Mannich derivatives are used as versatile intermedi- hedron Lett. 34 6921; (e) Bravo P, Fustero S, Guidetti ate in target synthesis of hypnotic, antiinflammatory M, Volonterio A and Zanda M 1999 J. Org. Chem. and anticonvulsant molecules. The relative position of 64 8731 Mannich side chain in a molecule plays a crucial role 7. 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