Synthesis, design, and assessment of novel morpholine-derived Mannich bases as multifunctional agents for the potential enzyme inhibitory properties including docking study.

The synthesized Schiff Bases were reacted with formaldehyde and secondary amine such as 2,6-dimethylmorpholine to afford N-Mannich bases through the Mannich reaction. 3-Substitued-4-(4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (4) were treated with 2,6-dimethylmorpholine in the presence of formaldehyde to synthesize eight new 1-(2,6-dimethylmorpholino-4-yl-methyl)-3-substitued-4-(4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (4a-h). The structures of the synthesized eight new compounds were characterized using IR, 1H NMR, 13C NMR, and HR-MS spectroscopic methods. Synthesized compounds inhibitory activity determined against the acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and glutathione S-transferase (GST) enzymes with Ki values in the range 25.23-42.19 µM for AChE, 19.37-34.22 µM for BChE, and 21.84-41.14 µM for GST, respectively. Binding scores of most active inhibitors against AChE, BChE, and GST enzymes were detected as -10.294 kcal/mol, -9.562 kcal/mol, and -7.112 kcal/mol, respectively. The hydroxybenzylidene moiety of the most active inhibitors caused to inhibition of the enzymes through hydrophobic interaction and hydrogen bond.

Second Generation of Mannich Base-Type Derivatives with in Vivo Activity against Trypanosoma cruzi.

Chagas disease is a potentially life-threatening and neglected tropical disease caused by Trypanosoma cruzi. One of the most important challenges related to Chagas disease is the search for new, safe, effective, and affordable drugs since the current therapeutic arsenal is inadequate and insufficient. Here, we report a simple and cost-effective synthesis and the biological evaluation of the second generation of Mannich base-type derivatives. Compounds 7, 9, and 10 showed improved in vitro efficiency and lower toxicity than benznidazole, in addition to no genotoxicity; thus, they were applied in in vivo assays to assess their activity in both acute and chronic phases of the disease. Compound 10 presented a similar profile to benznidazole from the parasitological perspective but also yielded encouraging data, as no toxicity was observed. Moreover, compound 9 showed lower parasitaemia and higher curative rates than benznidazole, also with lower toxicity in both acute and chronic phases. Therefore, further studies should be considered to optimize compound 9 to promote its further preclinical evaluation.

Molecular docking study, synthesis and biological evaluation of Mannich bases as Hsp90 inhibitors.

The ubiquitously expressed heat shock protein 90 is an encouraging target for the development of novel anticancer agents. In a program directed towards uncovering novel chemical scaffolds against Hsp90, we performed molecular docking studies using Tripos-Sybyl drug designing software by including the required conserved water molecules. The results of the docking studies predicted Mannich bases derived from 2,4-dihydroxy acetophenone/5-chloro 2,4-dihydroxy acetophenone as potential Hsp90 inhibitors. Subsequently, a few of them were synthesized (1-6) and characterized by IR, (1)H NMR, (13)C NMR and mass spectral analysis. The synthesized Mannich compounds were evaluated for their potential to suppress Hsp90 ATPase activity by the colorimetric Malachite green assay. Subsequently, the molecules were screened for their antiproilferative effect against PC3 pancreatic carcinoma cells by adopting the 3-(4,5-dimethythiazol- 2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay method. The activity profile of the identified derivatives correlated well with their docking results.

Interaction of piperidin derivative of Mannich base with DPPC liposomes.

The long chain Mannich bases, especially with the piperidine and morpholine groups, display very promising antimicrobial activity. In order to extend our knowledge on their impact on biological systems, we examined the interactions of the 5-pentadecyl-2-((piperidin-1-yl)methyl)phenol (PPDP) with model lipid membrane by means of differential scanning calorimetry (DSC) and fluorescence measurements. The small unilamellar vesicles of dipalmitoylophosphatidylcholine (DPPC) with different piperidine Mannich base concentration were investigated as a function of the increase of temperature. The phase separation accompanied by the rise of the transition enthalpy of both subcomponents, the increase of the function of the GP values of Laurdan versus the wavelength of excitation in the gel phase of PPDP/DPPC systems, and no remarkable differences in the fluorescence anisotropy of PPDP molecules in lipid environment for different mixtures of PPDP/DPPC was observed. Additionally, it was shown that PPDP itself interdigitated in solid state.

Protease-catalysed direct asymmetric Mannich reaction in organic solvent.

We reported the first enzyme-catalysed, direct, three-component asymmetric Mannich reaction using protease type XIV from Streptomyces griseus (SGP) in acetonitrile. Yields of up to 92% with enantioselectivities of up to 88% e.e. and diastereoselectivities of up to 92:8 (syn:anti) were achieved under the optimised conditions. This enzyme's catalytic promiscuity expands the application of this biocatalyst and provides a potential alternative method for asymmetric Mannich reactions.

Antimalarial activity of Mannich bases derived from 4-(7'-bromo-1',5'-naphthyridin-4'-ylamino)phenol and 4-(7'-trifluoromethylquinolin-4'-ylamino)phenol against Plasmodium falciparum in vitro.

Mono- and di-Mannich bases derived from 4-(7'-bromo-1',5'-naphthyridin-4'-ylamino)phenol and 4-(7'-trifluoromethylquinolin-4'-ylamino)phenol were assayed for antimalarial activity (using an in vitro radioisotopic technique) against two isolates of Plasmodium falciparum. Many from these two series of compounds had an IC50 value (concentration of compound causing 50% inhibition of 3H-hypoxanthine incorporation) comparable to or better than those of mefloquine and amodiaquine, for both a chloroquine-sensitive isolate (FCQ-27) and the chloroquine-resistant isolate (K1). At least one compound, 2,6-bis (piperidin-1''-ylmethyl)-4-(7'-trifluoromethylquinolin -4'-ylamino)phenol (TN112), showed significant superior activity to the three antimalarials chloroquine, mefloquine and amodiaquine against both isolates. (Statistically superior activity compared to these three antimalarials was found for TN112, except that against the K1 isolate its activity was just outside the range of significance relative to mefloquine.) Some of the 7-bromo-1,5-naphthyridine Mannich bases were appreciably less toxic in mice than amodiaquine.

Binding (in vitro) of some antimitotic isatin derivatives to human serum albumin.

The binding of isatin and its mustard N-Mannich base, considerably biologically active compounds, to human serum albumin has been studied by equilibrium dialysis and ultrafiltration. The influences of ligand and macromolecule concentration, temperature and pH of the incubation medium have been demonstrated. The Scatchard plot of isatin binding to albumin shows a biphasic curve which indicates the presence of at least two different binding sites on albumin molecule. One site with a higher affinity, K1 = 2.25 X 10(3) M and n1= 25, and the other site with a lower affinity, i.e. higher capacity. In the cases of mustard Mannich base we could demonstrate the same type of curve, K1 = 2.20 X 10(5) M and n1 = 1.0, whereas another site has a lower affinity and greater number of binding sites.