Synthesis of pyrazinamide Mannich bases and its antitubercular properties

A series of pyrazinamide (PAZ) Mannich bases has been synthesized by reacting PAZ, formaldehyde, and various substituted piperazines using microwave irradiation with the yield ranging from 46% to 86%. The synthesized compounds were evaluated for antimycobacterial activity in vitro and in vivo against Mycobacterium tuberculosis H37Rv (MTB). Among the synthesized compounds, 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-4-((pyrazine-2-carboxamido)methyl)piperazin-1-yl)-4-oxoquinoline-3-carboxylic acid (17) was found to be the most active compound in vitro with MIC of 0.39 and 0.2 microg/mL against MTB and multidrug-resistant MTB, respectively. In the in vivo animal model 17 decreased the bacterial load in lung and spleen tissues with 1.86 and 1.66-log10 protections, respectively.     

Activity of Mannich bases of 7-hydroxycoumarin against Flaviviridae

Some Mannich bases of 7-hydroxycoumarin (2) and their simple derivatives (3 and 4) were prepared and tested against viruses containing single-stranded, positive-sense RNA genomes (ssRNA(+)). This study was directed toward Flaviviridae and, in particular, HCV surrogate viruses (BVDV, YFV). The 7-hydroxy derivatives 2 were generally devoid of activity, but when position 7 was propylated, the resulting 7-propyloxy derivatives 3 were in some cases endowed with an interesting activity against BVDV. The formation of 7-benzoyl derivatives 4 gave compounds generally lacking in activity against Flaviviridae, whereas the appearance of activity against RSV has been observed. Also some unsymmetrical methylene derivatives 5-7 (namely coumarins bridged to chromones or indoles) were found moderately active in antiviral tests. Derivatives 3 were submitted to a molecular modeling study using DNA polymerase of HCV as a target. The good correlation between calculated molecular modeling IC(50) and experimental EC(50) indicates that DNA polymerase is potentially involved in the inhibition of surrogate HCV viruses.     

Enzyme-assisted kinetic resolution of novel 2-naphthol Mannich bases

In an attempt to develop novel Selective Estrogen Receptor Modulators (SERMs) containing a chirality centre, simpler 1-((2-hydroxynaphthalen-1-yl)arylmethyl)piperidin-4-ol prototypes were synthesized as racemic mixtures via the Mannich reaction protocol from 2-naphthol, 4-piperidinol, and 10 different aromatic aldehydes. These 10 chiral Mannich bases were then resolved utilizing an enzyme-assisted chemo-, regio-, and enantioselective acetylation process. The enzyme (Novozyme 435^®; Lipase B from Candida Antarctica) displayed exclusive chemo- and regioselectivity in acetylating the test compounds; the optical enrichment was also achieved as evidenced by measurement of the optical rotation of the mono-acetylated product and unreacted dihydroxy compound.     

Effect of Mannich bases on some plant pathogenic fungi

3-(2-Pyridyl)-3-iminoisatin, 1-piperidinomethyl-3-(2-pyridyl)-3-iminoisatin, and 1-acetyl-3-(2-pyridyl)-3-iminoisatin affect spore germination ofAlternaria alternata, A. carthemi, Curvularia lunata, Fusarium oxysporum f.sp.cieri andF. udum and influence the development of powdery mildew (Erysiphe pisi) on pea under glasshouse condition as well as conidial germination ofE. pisi on excised pea leaves. Spore germination was inhibited in the sequence 1-acetyl-3-(2-pyridyl)-3-iminoisatin > 1-piperidinomethyl-3-(2-pyridyl)-3-iminoisatin > 3-(2-pyridyl)-3-iminoisatin followed the order accordingly. The powdery mildew development and conidial germination ofE. pisi 1-piperidinomethyl-3-(2-pyridyl)-3-iminoisatin > 1-acetyl-3-(2-pyridyl)-3-iminoisatin > 3-(2-pyridyl)-3-iminoisatin. The chemicals were compared with commonly used antifungal fungicides.     

New phenolic Mannich bases with piperazines and their bioactivities

In this study, new Mannich bases, 2-(4-hydroxy-3-methoxy-5-((substitutedpiperazin-1-yl)methyl)benzylidene)-2,3-dihydro-1H-inden-1-one (1, 2, 4, 5, 8), 2-(3-((substituted)piperazin-1-yl)methyl)-4-hydroxy-5-methoxybenzylidene)-2,3-dihydro-1H-inden-1-one (3, 6, 7) were synthesized with the reaction of vanilin derived chalcone compound (2-(4-hydroxy-3-methoxybenzylidene)indan-1-one), paraformaldehyde and suitable amine in 1:1.2:1 mol ratios. Amine part was changed as N-methylpiperazine (1), N-phenylpiperazine (2), N-benzylpiperazine (3), 1-(2-methoxyphenyl)piperazine (4), 1-(3-methoxyphenyl)piperazine (5), 1-(2-fluorophenyl)piperazine (6), 1-(4-fluorophenyl)piperazine (7), and 1-(3-trifluoromethyl)phenyl piperazine (8). Compounds were evaluated in terms of cytotoxic/anticancer and CA inhibitory effects. According to the results obtained, the compounds 2 and 8 had the highest potency selectivity expression (PSE) values (60.6 and 19.2, respectively). On the other hand, the compounds 3 (Ki = 209.6 ± 70.2 pM) and 5 (Ki = 342.66 ± 63.72 pM) had the lowest Ki values in CA inhibition experiments towards hCA I and hCA II, respectively.In conclusion, the compounds 2 (with cytotoxic/anticancer activity), 3 (with hCA I inhibiting activity) and 5 (with hCA II inhibiting activity) can be leading compounds of the study for further designs and evaluations.     

QSAR study on antibacterial activity of sulphonamides and derived Mannich bases

The paper describes synthesis and comparative study on antibacterial activities of sulphonamides and Mannich bases derived from them. The compounds were screened for their antibacterial activity against various gram-positive and gram-negative bacteria and were analyzed statistically. The results have shown that the compounds are quiet active against pathogens under study and were nontoxic.     

Conventional and microwave assisted synthesis of pyrazolone Mannich bases possessing anti-inflammatory,analgesic, ulcerogenic effect and antimicrobial properties

In the present study, an efficient synthesis of some Mannich base of 5-methyl-2-[(2-oxo-2H-chromen-3-yl)carbonyl]-2,4-dihydro-3H-pyrazol-3-one (4a–j) have been described by using conventional and non-conventional (microwave) techniques. Microwave assisted reactions showed that require shorter reaction time and good yield. The newly synthesized compounds were screened for their anti-inflammatory, analgesic activity, antioxidant, and antibacterial effects were compared with standard drug. Among the compounds studied, compound (4f) showing nearly equipotent anti-inflammatory and analgesic activity than the standard drug (indomethacin), along with minimum ulcerogenic index. Compounds (4b and 4i) showing 1.06 times more active than ciprofloxacin against tested Gram-negative bacteria.     

Synthesis and in vitro study of novel Mannich bases as antibacterial agents

A series of novel Mannich bases derived from 5-chloro-2-methoxybenzamide and sulfonamides/amines have been synthesised and the antibacterial activities were evaluated against various Gram positive and Gram negative strains of bacteria. Some of the synthesized compounds showed superior in vitro activities as compared to their parent sulfonamides.     

Antioxidant and antiproliferative activities of hydroxyl-substituted Schiff bases

Eight hydroxyl-substituted Schiff bases with the different number and position of hydroxyl group on the two asymmetric aromatic rings (A and B rings) were prepared by the reaction between the corresponding aromatic aldehyde and aniline. Their antioxidant effects against the stable galvinoxyl radical (GO) in ethyl acetate and methanol, and 2,2′-azobis(2-amidinopropane hydrochloride) (AAPH)-induced DNA strand breakage, and their antiproliferative effects on human hepatoma HepG2 cells, were investigated. Structure–activity relationship analysis demonstrates that o-dihydroxyl groups on the aromatic A ring and 4-hydroxyl group attached to the aromatic B ring contribute critically to the antioxidant and antiproliferative activities.     

In vitro study of some medicinally important Mannich bases derived from antitubercular agent

Biologically active Mannich bases with heteroaromatic ring system have been synthesised employing Mannich reaction of isonicotinyl hydrazide with various sulphonamides/secondary amines. They were analysed by elemental analysis and characterized by uv, ir, 1H nmr spectroscopic studies. The Mannich bases were screened for their antibacterial activity against various gram positive and gram negative bacteria and were analyzed statistically. The results have shown that the compounds are quiet active against pathogens under study and were nontoxic.     

Synthesis and bioactivities of halogen bearing phenolic chalcones and their corresponding bis Mannich bases

Abstract

Phenolic bis Mannich bases having the chemical structure of 1-[3,5-bis-aminomethyl-4-hydroxyphenyl]-3-(4-halogenophenyl)-2-propen-1-ones (1a-c, 2a-c, 3a-c) were synthesized (Numbers 1, 2, and 3 represent fluorine, chlorine, and bromine bearing compounds, respectively, while a, b, and c letters represent the compounds having piperidine, morpholine, and N-methyl piperazine) and their cytotoxic and carbonic anhydrase (CA, EC 4.2.1.1) enzyme inhibitory effects were evaluated. Lead compounds should possess both marked cytotoxic potencies and selective toxicity for tumors. To reflect this potency, PSE values of the compounds were calculated. According to PSE values, the compounds 2b and 3b may serve as lead molecules for further anticancer drug candidate developments. Although the compounds showed a low inhibition potency toward hCA I (25–43%) and hCA II (6–25%) isoforms at 10?μM concentration of inhibitor, the compounds were more selective (1.5–5.2 times) toward hCA I isoenzyme. It seems that the compounds need molecular modifications for the development of better CA inhibitors.     

Synthesis,antiproliferative and antimicrobial activity of new Mannich bases bearing 1,2,4-triazole moiety

Abstract

This study presents the synthesis, antiproliferative and antimicrobial evaluation of a new series of Mannich base derivatives containing 1,2,4-triazole system. New compounds were prepared by the reaction of 4,5-disubstituted 1,2,4-triazole-3-thiones with formaldehyde and various amines. The structures of the prepared compounds were confirmed by means of ¹H NMR, ¹³C NMR and elemental analyses. Twelve compounds were evaluated for their in vitro antiproliferative activities against six chosen cancer cell lines. All synthesized compounds were screened for their in vitro antimicrobial activity by using the agar dilution technique. For 17 potentially active compounds, their antibacterial activity was confirmed on the basis of MIC (minimal inhibitory concentration) by broth microdilution method using the reference Gram-positive and Gram-negative bacterial strains.     

Synthetic indole Mannich bases: Their ability to modulate in vitro cellular immunity

The synthetic indole Mannich bases 1–13 have been investigated for their ability to modulate immune responses measured in vitro. These activities were based on monitoring their affects on T-lymphocyte proliferation, reactive oxygen species (ROS), IL (interleukin)-2, IL-4, and nitric oxide production. Compound 5 was found to be the most potent immunomodulator in this context. Four of the synthesized compounds, 5, 11, 12, and 13, have significant potent inhibitory effects on T-cell proliferation, IL-4, and nitric oxide production. However, none of the thirteen indole compounds exerted any activity against ROS production.     

Inhibitory effects of isatin Mannich bases on carbonic anhydrases,acetylcholinesterase, and butyrylcholinesterase

The effects of isatin Mannich bases incorporating (1-[piperidin-1-yl (P1)/morpholin-4-yl (P2)/N-methylpiperazin-1-yl (P3)]methyl)-1H-indole-2,3-dione) moieties against human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoenzymes hCA I and hCA II, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzymes were evaluated. P1–P3 demonstrated impressive inhibition profiles against AChE and BChE and also inhibited both CAs at nanomolar level. These inhibitory effects were more powerful in all cases than the reference compounds used for all these enzymes. This study suggests that isatin Mannich bases P1–P3 are good candidate compounds especially for the development of new cholinesterase inhibitors since they were 2.2–5.9 times better inhibitors than clinically used drug Tacrine.     

The inhibitory effects of phenolic Mannich bases on carbonic anhydrase I and II isoenzymes

Phenolic mono Mannich bases [2-[4-hydroxy-3-(aminomethyl)benzylidene]-2,3-dihydro-1H-inden-1-one (8–15)] and bis Mannich bases [2-[4-hydroxy-3,5-bis(aminomethyl)benzylidene]-2, 3-dihydro-1H-inden-1-one (2–7)] were synthesized starting from 2-(4-hydroxybenzylidene)-2, 3-dihydro-inden-1-one (1). This study was designed in order to investigate the carbonic anhydrase (CA, EC 4.2.1.1) inhibitory properties of a library of compounds incorporating the phenol functional group. All prepared compounds showed a low inhibition percentages on both human (h) isoforms hCA I and hCA II compared to the reference sulfonamide acetazolamide. Mannich bases 2–15 had lower inhibition percentages than the compound 1 on hCA I and hCA II, except compound 14, which is a Mannich base derivative of dipropylamine, which had a similar inhibitory power as compound 1 on hCA II. All compounds synthesized 1–15 were 1.3–1.9 times more effective on hCA II comparing with the effectivenes of the compounds on hCA I.     

Metal complexes of a new class of polydentate Mannich bases: Synthesis and spectroscopic characterisation

A new class of polydentate Mannich bases featuring an N₂S₂ donor system, bis((2-mercapto-N-phenylacetamido)methyl)phosphinic acid H₃L¹ and bis((2-mercapto-N-propylacetamido)methyl)phosphinic acid H₃L², has been synthesised from condensation of phosphinic acid and paraformaldehyde with 2-mercaptophenylacetamide W1 and 2-mercaptopropylacetamide W2, respectively. Monomeric complexes of these ligands, of general formula K₂[Cr^III(Lⁿ)Cl₂], K₃[M′^II(Lⁿ)Cl₂] and K[M(Lⁿ)] (M′ = Mn(II) or Fe(II); M = Co(II), Ni(II), Cu(II), Zn(II), Cd(II) or Hg(II); n = 1, 2) are reported. The structures of new ligands, mode of bonding and overall geometry of the complexes were determined through IR, UV–Vis, NMR, and mass spectral studies, magnetic moment measurements, elemental analysis, metal content, and conductance. These studies revealed octahedral geometries for the Cr(III), Mn(II) and Fe(II) complexes, square planar for Ni(II) and Cu(II) complexes and tetrahedral for the Co(II), Zn(II), Cd(II) and Hg(II) complexes. Complex formation studies via molar ratio in DMF solution were consistent to those found in the solid complexes with a ratio of (M:L) as (1:1).     

Synthesis and biological activity of Schiff and Mannich bases bearing 2,4-dichloro-5-fluorophenyl moiety

A series of 2,4-dichloro-5-fluorophenyl bearing Mannich base (4 and 5) was prepared from triazole Schiff bases (3) by aminomethylation with formaldehyde and secondary/substituted primary amines. All newly synthesized compounds were screened for their antimicrobial activity. Compounds 3c, 4c, 4e and 4f exhibited promising antibacterial and compounds 3c, 5c, 5e and 5f showed good antifungal activity.     

Antioxidant status and purine bases in carotid artery plaque

Free radical excess and oxidative stress are implicated in the formation and progression of atherosclerotic plaque through actions on susceptible vascular cells, such as by activating xanthine oxidase. Purine bases and other antioxidant compounds could play important protective roles in atherogenesis, as could nonenzymatic low molecular weight thiol defenses, not previously evaluated in carotid artery plaque. Therefore, we measured purine catabolites (hypoxanthine, xanthine, uric acid, allantoin) and antioxidant compounds (total sulphydryl groups, homocysteine, cysteine, and glutathione) in advanced carotid artery plaque and found a high ratio of allantoin to uric acid, suggesting a ongoing local oxidative stress.     

Mechanism-based inactivation of thioredoxin reductase from Plasmodium falciparum by Mannich bases. Implication for cytotoxicity

Thioredoxin reductase (TrxR) is the homodimeric flavoenzyme that catalyzes reduction of thioredoxin disulfide (Trx). For Plasmodium falciparum, a causative agent of tropical malaria, TrxR is an essential protein which has been validated as a drug target. The high-throughput screening of 350000 compounds has identified Mannich bases as a new class of TrxR mechanism-based inhibitors. During catalysis, TrxR conducts reducing equivalents from the NADPH-reduced flavin to Trx via the two redox-active cysteine pairs, Cys88-Cys93 and Cys535'-Cys540', referred to as N-terminal and C-terminal cysteine pairs. The structures of unsaturated Mannich bases suggested that they could act as bisalkylating agents leading to a macrocycle that involves both C-terminal cysteines of TrxR. To confirm this hypothesis, different Mannich bases possessing one or two electrophilic centers were synthesized and first studied in detail using glutathione as a model thiol. Michael addition of glutathione to the double bond of an unsaturated Mannich base (3a) occurs readily at physiological pH. Elimination of the amino group, promoted by base-catalyzed enolization of the ketone, is followed by addition of a second nucleophile. The intermediate formed in this reaction is an alpha,beta-unsaturated ketone that can react rapidly with a second thiol. When studying TrxR as a target of Mannich bases, we took advantage of the fact that the charge-transfer complex formed between the thiolate of Cys88 and the flavin in the reduced enzyme can be observed spectroscopically. The data show that it is the C-terminal Cys 535'-Cys540' pair rather than the N-terminal Cys88-Cys93 pair that is modified by the inhibitor. Although alkylated TrxR is unable to turn over its natural substrate Trx, it can reduce low M(r) electron acceptors such as methyl methanethiolsulfonate by using its unmodified N-terminal thiols. On the basis of results with chemically distinct Mannich bases, a detailed mechanism for the inactivation of TrxR is proposed.     

Mannich bases of scutellarein as thrombin-inhibitors: Design,synthesis, biological activity and solubility

Two series of 8-aminomethylated derivatives were prepared by Mannich reaction of scutellarein (2) with appropriate aliphatic amines, alicyclic amines and formaldehyde. All the compounds were tested for their thrombin inhibition activity through the analyzation of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen (FIB). The antioxidant activities of these target products were assessed by 1,1-diphenyl-2-picrylhydrazyl radical 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH) assay using 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay method and the solubility were assessed by ultraviolet (UV). The results showed that morpholinyl aminomethylene substituent derivative (3d) demonstrated stronger anticoagulant activity, better water solubility and good antioxidant activity compared with scutellarein (2), which warrants further development as a agent for ischemic cerebrovascular disease treatment.