Mono Mannich Bases Research Articles

Synthesis and biological evaluation of some new mono Mannich bases with piperazines as possible anticancer agents and carbonic anhydrase inhibitors

New mono Mannich bases, (2-(4-hydroxy-3-((4-substituephenylpiperazin-1-yl)methyl)benzylidene)-2,3-dihydro-1H-inden-1-one), were prepared to evaluate their cytotoxic/anticancer properties and also their inhibitory effects on human carbonic anhydrase I and II isoenzymes (hCA I and II). Amine part was changed as [N-phenylpiperazine (1), N-benzylpiperazine (2), 1-(2-fluorophenyl)piperazine (3), 1-(4-fluorophenyl)piperazine (4), 1-(2-methoxyphenyl)piperazine (5)]. The structure of the synthesized compounds was characterized by 1H NMR, 13C NMR and HRMS spectra. Cytotoxicity results of the series pointed out that the compound 4 had the highest tumor selectivity value (TS: 59.4) possibly by inducing necrotic cell death in series. Additionally, all compounds synthesized showed a good inhibition profile towards hCA I and II isoenzymes with the Ki values between 29.6 and 58.4 nM and 38.1–69.7 nM, respectively. These values were lower than the reference compound AZA. However, it seems that the compounds 4 and 2 can be considered as lead compounds of CA studies with the lowest Ki values in series for further designs.

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.

Crystal structure of 3-(thiophen-2-yl-carbonyl)-4-(thiophen-2-yl)-1-isopropyl-4-piperidinol, C17H21NO2S2

Abstract C17H21NO2S2, P1̅ (no. 2), a = 5.9254(2) Å, b = 8.9579(2) Å, c = 16.6787(4) Å, α = 92.570(1)°, β = 99.158(2)°, γ = 98.441(2)°, V = 862.4 Å3, Z = 2, Rgt(F) = 0.0557, wRref(F2) = 0.1477, T = 293 K.

Antifungal activity of some mono, bis and quaternary Mannich bases derived from acetophenone.

The development of resistance to current antifungal therapeutics drives search for new effective agents. Some Mannich bases have antifungal activity, but no information is available regarding the antifungal activity of acetophenone derived Mannich bases. Mono Mannich bases of acetophenone 1-3 were synthesized and converted into their corresponding bis derivatives, 5-7. Representative quaternary derivatives 4 and 8 were also synthesized. Antifungal activities of the compounds were evaluated using some yeasts and dermatophytes in vitro. Mono Mannich base 3 and quaternary compounds 4 and 8 were found to be 2-16 times more potent than the reference compound amphotericin B against dermatophytes: Trichophyton rubrum, Trichophyton mentagrophytes, and Microsporum canis. Compounds 4 and 8 were also found to be 2 times more effective compared with amphotericin B against the yeast Saccharomyces cerevisiae. Quaternization procedure improved the biological activity dramatically, whereas conversion of mono Mannich bases to corresponding bis derivatives generally did not affect antifungal activity. Our results suggest that acetophenone derived mono Mannich base 3 and quaternary derivatives 4 and 8 may serve as leading compounds for further studies to develop new antifungal agents with their highly potent antifungal activity.

Cytotoxic activities of some mono and bis Mannich bases derived from acetophenone in brine shrimp bioassay.

Some mono Mannich bases (1-phenyl-3-amino-1-propanone salts) and bis Mannich bases (1-phenyl-3-amino-2-amino-methyl-1-propanone salts) derived from acetophenone and a few representative quaternary derivatives were synthesised and their cytotoxicity was tested using the brine shrimp bioassay. This assay may serve as an intermediate test before further in vivo animal experiments in large scale, since brine shrimp nauplii as whole organisms were used in this test. Mono Mannich bases were generally more cytotoxic than their corresponding bis Mannich bases. Mannich bases synthesised were cytotoxic in both brine shrimp bioassay in this study and cell culture tests using Jurkat and Renca cells in a previous study. However, the order of the cytotoxic potency of the compounds were reverse, which may result from faster deamination of bis derivatives than optimal level, and different species and test media used in the two test systems. Faster deamination of bis derivatives might have led to elimination of active metabolites before reaching its target. The cytotoxicity of the compounds might have been altered by amino acids and proteins present in cell culture medium but not in sea water used in brine shrimp bioassay affecting their transport through the cell membrane and metabolism in the cell by binding with the compounds. With higher cytotoxic activity compared with 5-fluorouracil (CAS 51-21-8) in brine shrimp bioassay, mono Mannich base 1 and its quaternary derivative 4 and quaternary bis derivative 8 seem to be candidate compounds for further drug design.

Effect of acetophenone derived Mannich bases on cellular glutathione level in Jurkat cells. A possible mechanism of action.

The effect of the acetophenone derived mono Mannich bases 1-3 and bis Mannich base 7 (bis derivative of compound 3) on cellular glutathione level was investigated in Jurkat cells. The cells were exposed to the compounds in phosphate buffered saline for 1 h in 37 degrees C with gentle shaking and then glutathione level was measured. Especially, mono Mannich base 3 and its bis derivative 7 decreased total glutathione level in a dose-dependent manner. The results provide further support for the thiol alkylation mechanism explaining the cytotoxic activity of Mannich bases.

Syntheses and stability studies of some Mannich bases of acetophenones and evaluation of their cytotoxicity against Jurkat cells.

Mannich bases, namely 1-aryl-3-dimethylamino-1-propanone hydrochlorides (Ia-f) as mono-Mannich bases (series I), bis(beta-aroylethyl)ethylamine hydrochlorides (IIa, IIb, IId, IIe) as bis-Mannich bases (series II), 3-aroyl-4-aryl-1-ethyl-4-piperidinol hydrochlorides (series III), which are structural isomers of bis derivatives and some representative quaternary salts (Ig, IIIf, IIIg), were synthesized to investigate the effect of chemical structure and ring substituents on cytotoxic activity in Jurkat cells. Stability studies of some representative compounds have also been realised. Compounds IIb, IId, IIe, and IIIe were reported for the first time. Id-g, IIa, IId, IIe, IIIf,g were 1.25-6.55 times more potent than 5-fluorouracil (CAS 51-21-8). However, the cytotoxic activity of the most potent compounds. Ig and IIIf, were one fifth of that of melphalan (CAS 148-82-3). The formation of compound IV during the stability studies of Ig, IIa, and IIIf suggested that they may be thiol alkylators. Bis-Mannich base IIa in nonsubstituted derivatives, piperidinol derivative IIIb in methyl substituted compounds, mono derivative Id in chloro substituted compounds were the most potent compounds when the cytotoxicity of the compound series which have the same substituents in benzene ring are compared. Replacement of the benzene with thiophene improved the cytotoxicity in both series I and II. Quaternization procedure also increased the cytotoxicity in both series I and III. Quaternary derivatives seem to be promising compounds for further studies to develop new anticancer drugs.

Antimicrobial evaluation of some Mannich bases of acetophenones and representative quaternary derivatives.

1-Aryl-3-dimethylamino-1-propanone hydrochlorides Ia-f (series I) as mono-Mannich bases bis(beta-aroylethyl)ethylamine hydrochlorides IIa, IIb, IId, IIe (series II) as bis-Mannich bases, 3-aroyl-4-aryl-1-ethyl-4-piperidinol hydrochlorides (structural isomer of bis derivatives IIIa-e, series III), and some of their representative quaternary salts (Ig, IIIf, IIIg) were synthesized. Antimicrobial activities of the compounds were evaluated against some bacteria and fungi. Series I and III showed antimicrobial activity against gram positive bacteria. All series demonstrated activity against fungi, however, they generally did not affect gram negative bacteria at the concentration range tested (2-64 micrograms/ml). Quaternisation procedure improved the bioactivity in compound IIIa for antibacterial activity and in compounds IIIa and IIIb for antifungal activity against Trichophyton rubrum and Mycosporium canis. There was no relationship between Hammett values of the aryl substituents and bioactivities in series III. The mono-Mannich bases of series I had better antimicrobial activities than bis-Mannich bases of series II. Compounds Ia, If, IIId had equal and compounds If and IIIf had higher antibacterial activities compared to the reference drug, streptomycin (CAS 57-92-1), against various gram positive bacteria. On the other hand, compounds Ia, IIIa, IIIc, IIIe, IIIf, and IIIg had equal and If, IIId, IIIf, IIIg had higher antifungal activity compared to the reference drug, amphotericin-B (CAS 1397-89-3), against various fungi. To conclude, the compounds of series III, having both marked antifungal and antibacterial activities, may serve as candidate compounds for further studies. Especially compound IIIf may serve as a model compound to develop new agents against dermatophytes.

Biological Evaluation and Structure-Activity Relationships of Bis-(3-aryl-3-oxo-propyl)-methylamine Hydrochlorides and 4-Aryl-3-arylcarbonyl-1-methyl-4-piperidinol Hy-drochlorides as Potential Cytotoxic Agents and their Alkylating Ability towards Cellular Glutathione in Human Leukemic T Cells

Various bis (3-aryl-3-oxo-propyl)methylamine hydrochlorides 1 and their corresponding structural and non-classical isomers 4-aryl-3-arylcarbonyl-1-methyl-4-piperidinols 3 were evaluated against human leukemic T (Jurkat) cells and found to possess significant cytotoxicity. Among the series 1 (bis-Mannich bases) and 3 (corresponding piperidinols), compounds la, 1c and 1e showed cytotoxic potency which was approximately 1.6, 3.7 and 3.4 times that of the reference drug 5-fluorouracil, respectively. Except for compound 1d, conversion of bis-Mannich bases to their corresponding piperidinols 3a, 3b and 3e lowered the potency. Besides chloro derivative 1d, bis-Mannich bases displayed greater cytotoxicity compared with their mono-Mannich bases, series 5. Representative bis-Mannich bases (1a, 1e) and piperidinols (3a, 3e) decreased the glutathione level of Jurkat cells. Molecular modeling was utilized in order to evaluate whether the shape, size, critical volume, solvent accessible area and partition coefficient of the different compounds had contributed to the varying potencies observed. Bis-Mannich bases 1a, 1c and 1e may serve as candidate anticancer agents for future development.

Evaluation of the Cytotoxicity of Some Mono-Mannich Bases and Their Corresponding Azine Derivatives against Androgen-independent Prostate Cancer Cells

Mono-Mannich bases derived from acetophenones, 1-aryl-3-amino- 1 -propanone hydrochlorides (Igl-Ig4), and their corresponding azine derivatives, N, N'-bis(3-amino-l-aryl-propylidene) hydrazine dihydrochlorides (DI-D4), were designed and synthesized as cellular thiol alkylating agents. The aryl portion was replaced by a phenyl group in Ig1, Ig2, Ig3, D1, D2, and D3, and by a p-hydroxyphenyl group in Ig4 and D4. The amine side chain was replaced by a dimethylamine group in Igl, D1, Ig4 and D4, by a piperidine group in Ig2 and D2, and by a morpholine group in Ig3 and D3. The cytotoxic activity of the compounds was tested against the androgen-independent prostate cancer cell line PC-3. The relationship between cytotoxicity and pKa value of the amine group and partition coefficients of the compounds was also investigated. Azine derivative D4 was found to be the most potent among all the compounds tested and the cytotoxicity increased 1.73 fold compared with the mono-Mannich base Ig4 in PC-3 cells. On the other hand, conversion of mono-Mannich bases Igl-Ig3 to their corresponding azine derivatives DI-D3 decreased the cytotoxicity considerably. Substitution of the hydroxyl group at the para position of the aromatic ring in azine derivative D4 increased the cytotoxicity, and a rational explanation in this regard is described in length. The results emerged from this investigation guide the future expansion of these series of compounds.

Synthesis of some Mannich bases with dimethylamine and their hydrazones and evaluation of their cytotoxicity against Jurkat cells

1-Aryl-3-dimethylamino-1-propanone hydrochlorides type mono Mannich bases, D series, and corresponding hydrazone derivatives, K series, were synthesized and their cytotoxicity was tested against Jurkat cells (transformed human T-lymphocytes). The aryl part was changed as phenyl in D1 and K1, 4-methylphenyl in D2 and K2, 4-methoxyphenyl in D3 and K3, 4-hydroxyphenyl in D4 and K4, 4-chlorophenyl in D5 and K5, 3-methoxyphenyl in D6 and K6, 4-fluorophenyl in D7 and K7, 4-bromophenyl in D8 and K8, 3-hydroxyphenyl in D9 and K9, and 2-acetylthiophene in D10 and K10. Of the compounds synthesized, K2, K3, K5, K6, K7, K8, K9, and K10 are reported for the first time. Cytotoxic activities of the D and K series were compared with each other to see alterations in bioactivity depending on the chemical structures in Jurkat cells. Cytotoxicities of the compounds synthesized were also compared with the reference compound, 5-fluorouracil (CAS 148-82-3). Mono Mannich bases, D1 (3.60 times), D2 (4.45 times), D3 (2.46 times), D4 (3.52 times), D5 (5.18 times), D6 (3.20 times), D7 (3.23 times), D8 (3.95 times), D9 (3.36 times) and D10 (3.99 times) had 2.46-5.18 times higher cytotoxic potency than the reference compound 5-fluorouracil against Jurkat cells, while hydrazones K1 (4.92 times), K2 (4.65 times), K3 (6.04 times), K4 (6.34 times), K5 (4.67 times), K6 (5.12 times), K7 (5.39 times), K8 (8.31 times), K9 (4.65 times) and K10 (8.65 times) had 4.65-8.65 times higher cytotoxic potency than the reference compound 5-fluorouracil against the same cell line. On the other hand, hydrazone compounds K1 (1.37 times), K3 (2.46 times), K4 (1.80 times), K6 (1.60 times), K7 (1.67 times), K8 (2.11 times), K9 (1.38 times), and K10 (2.17 times) had 1.37-2.46 times higher cytotoxic potency than their corresponding mono Mannich bases. The results of this study suggest that hydrazones were better compounds compared with the corresponding mono Mannich bases in terms of cytotoxicity, and they may serve as model compounds to develop new cytotoxic agents for further studies.

Biological Activity of 1-Aryl-3-phenethylamino-1-propanone Hydrochlorides and 3-Aroyl-4-aryl-1-phenethyl-4-piperidinols on PC-3 Cells and DNA Topoisomerase I Enzyme

A number of studies reported Mannich bases to manifest antimicrobial, cytotoxic, anticancer, anti-inflammatory, and anticonvulsant activities. A considerable number of therapeutically important cytotoxic compounds are active on DNA topoisomerases that regulate the DNA topology. In the present study we evaluated the biological activity of mono-Mannich bases, 1-aryl-3-phenethylamino-1-propanone hydrochlorides (1a-10a), and semicyclic mono-Mannich bases, 3-aroyl-4-aryl-1-phenethyl-4-piperidinols (1b-9b), synthesized in our laboratory. We employed androgen-independent human prostate cancer cells (PC-3) to assess the cytotoxicity of the compounds and extended the biological activity evaluation to cover supercoil relaxation assays of mammalian type I topoisomerases. Our results showed that the compounds had cytotoxicity within the 8.2-32.1 microM range, while two compounds gave rise to a comparable average value in topo I interference of 42% and 40% for 10a (with a hydroxy substituent on the phenyl ring from mono-Mannich bases) and 5b (with a fluoro substituent on the phenyl ring from the semicyclic mono-Mannich base series, piperidinols), respectively.

ChemInform Abstract: Unorthodox Rate Enhancement in the Mannich Reaction of para- Substituted Phenols Containing Electron-Withdrawing Groups.

Abstract Under classical conditions, the Mannich reaction of most substituted phenols with long chain secondary amines and formaldehyde is dramatically slowed after mono-Mannich base formation. With a powerful electron-withdrawing group in the para-position of the phenol, however, further reaction to form the di-Mannich base proceeds in virtually quantitative yields.

Synthesis and Antimalarial Activity of New Isotebuquine Analogues

Amodiaquine (AQ) and tebuquine are 4-aminoquinoline antimalarials with Mannich base side chain and are highly effective against chloroquine (CQ)-resistant strains of Plasmodium falciparum. Clinical use of AQ has been severely restricted due to hepatoxicity and agranulocytosis side effects associated with its long term use. Lysosomal accumulation and bioactivation to generate reactive quinoneimine metabolite are implicated to be the cause of the observed AQ toxicities. To avoid the quinoneimine formation and thus the toxicity, a series of isotebuquine analogues and their Nomega-oxides with hydroxy group meta to the amino rather than in para position of the aniline moiety were prepared. The new Mannich bases are highly active against both CQ-sensitive (D6) and -resistant (W2 and TM91C235) clones of P. falciparum with IC50 in the range of 0.3-120 ng/mL. New compounds are1000-fold less toxic (IC50 = 0.7-6 microg/mL) to mouse macrophage cell line than to parasite cell lines. Mono-Mannich bases are more active than bis-Mannich bases. Mono-Mannich base 1a (IC50 = 0.3 ng/mL) is 20-fold more active than the corresponding trifluoromethyl analogue 1b. No appreciable difference in either toxicity or efficacy were observed between the new Mannich bases (m-hydroxyaniline derivatives) 1a or 2a and the corresponding p-hydroxyaniline derivatives.

Biological Evaluation and Structure—Activity Relationships of Bis‐(3‐aryl‐3‐oxo‐propyl)methylamine Hydrochlorides and 4‐Aryl‐3‐arylcarbonyl‐1‐methyl‐4‐piperidinol Hydrochlorides as Potential Cytotoxic Agents and Their Alkylating Ability Towards Cellular Glutathione in Human Leukemic T Cells.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Evaluation of Antimicrobial Activities of Several Mannich Bases and Their Derivatives

The aim of this study was to evaluate the antimicrobial activities of several Mannich bases and their derivatives against pathogenic bacteria and fungi. 3-Dimethylamino-1-phenyl-1-propanone hydrochloride (Ig1) as mono-Mannich base, bis(beta-aroylethyl)methylamine hydrochlorides (B1, B5) as bis-Mannich bases, 3-aroyl-4-aryl-1-methyl-4-piperidinol hydrochlorides (C1, C5) as piperidinol derivatives, which are structural isomers of bis-Mannich bases, N,N'-Bis(3-dimethylamino-1-phenylpropylidene)hydra zine dihydrochlorides (D1) as azine derivative of mono-Mannich base Ig1, and some representative quaternary derivatives (Ig4 and C6), which are quaternary derivatives of Ig1 and C1, respectively, have been synthesized. Aryl parts were phenyl in B1 and C1, and 2-thienyl in B5 and C5. Bis-Mannich bases and quaternary Mannich bases were found to be effective antifungal derivatives. Quaternary mono-Mannich base Ig4 has shown twice the amount of higher antifungal potency against the human pathogenic fungus Microsporum canis compared with the reference drug amphotericin-B and it had equal potency against many other fungi species pathogenic in humans and plants. Ig4 was effective against Staphylococcus aureus among the bacteria tested. Preparation of bis-Mannich bases and qua ternization procedure seemed suitable chemical modifications to prepare effective antifungal compounds. Especially quaternary derivatives Ig4, and to some extent C6, seem to be model compounds to develop new antimicrobial agents for further studies.

Syntheses and Stability Studies of Some Mannich Bases of Acetophenones and Evaluation of Their Cytotoxicity Against Jurkat Cells.

Mannich bases, namely 1-aryl-3-di-methylamino-1-propanone hydrochlorides (Ia-f) as mono-Mannich bases (series I), bis(s-aroylethyl)ethylamine hydrochlorides (IIa, IIb, IId, IIe) as bis-Man-nich bases (series II), 3-aroyl-4-aryl-1-ethyl-4-piperidinol hydrochlorides (series III), which are structural isomers of bis derivatives and some representative quaternary salts (Ig, IIIf, IIIg ), were synthesized to investigate the effect of chemical structure and ring substituents on cytotoxic activity in Jurkat cells. Stability studies of some representative compounds have also been realised. Compounds IIb, IId, IIe, and IIIe were reported for the first time. Id-g, IIa, IId, IIe, IIIf,g were 1.25-6.55 times more potent than 5-fluorouracil (CAS 51-21-8). However, the cytotoxic activity of the most potent compounds, Ig and IIIf, were one fifth of that of melphalan (CAS 148-82-3). The formation of compound IV during the stability studies of Ig, IIa, and IIIf suggested that they may be thiol alkylators. Bis-Mannich base IIa in non-substituted derivatives, piperidinol derivative IIIb in methyl substituted compounds, mono derivative Id in chloro substituted compounds were the most potent compounds when the cytotoxicity of the compound series which have the same substituents in benzene ring are compared. Replacement of the benzene with thiophene improved the cytotoxicity in both series I and II. Quaternization procedure also increased the cytotoxicity in both series I and III. Quaternary derivatives seem to be promising compounds for further studies to develop new anticancer drugs.

Complexes of Benzene-1,2-diol Mannich Bases. I. Novel Hexacoordinate Zwitterionic Silicon(IV) Complexes

This paper reports the synthesis and characterization of a number of novel silicon(IV) complexes with a range of mono-Mannich bases of benzene-1,2-diol. Mannich bases of general structure 3-(dialkylaminomethyl)benzene-1,2-diol form zwitterionic 6-coordinate tris complexes with silicon(IV), eliminating the need for an external counter ion. These complexes exhibit marked differences in their ability to partition between an aqueous and organic phase compared with the analogous tris(benzene-1,2-diol) silicon(IV) complex. Mannich bases of diamines and benzene-1,2-diol will also complex to silicon; however, they result in more complicated polymeric structures.

Mannich bases of phenolic azobenzenes possessing cytotoxic activity

Summary A number of arylazophenols 1 were converted into the corresponding mono Mannich bases 2 from which two quaternary salts 3a,b and an ester 3c were prepared. A series of bis Mannich bases 4 were also synthesized. The angles (θ) made between one of the aryl rings and the adjacent azo linkage were determined by electronic absorption spectroscopy. X-ray crystallographic data were obtained for some of the Mannich bases. The compounds were evaluated against murine P388 D1 and L1210 cells and two human T-lymphocyte (Molt 4, CEM) lines, and most of the derivatives were also screened against a panel of human tumour cell lines. A number of correlations were noted between cytotoxicity and various physicochemical constants as well as some structural features determined by X-ray crystallography. Several of the Mannich bases were shown to have mutagenic properties using the A RK mutatest; the compounds in series 2 and 4 have the ability to penetrate the central nervous system, as revealed by their anticonvulsant properties. While series 2–4 have the potential to deaminate forming ortho quinone methides which would be capable of alkylating cellular thiols, the results of stability studies suggest that the bioactivities noted were due to the molecules per se.

Unorthodox rate enhancement in the Mannich reaction of para-substituted phenols containing electron-withdrawing groups

Under classical conditions, the Mannich reaction of most substituted phenols with long chain secondary amines and formaldehyde is dramatically slowed after mono-Mannich base formation. With a powerful electron-withdrawing group in the para-position of the phenol, however, further reaction to form the di-Mannich base proceeds in virtually quantitative yields.