Aminoalkyl Derivatives Research Articles

Synthesis and Biological Evaluation of O6-Aminoalkyl-Hispidol Analogs as Multifunctional Monoamine Oxidase-B Inhibitors towards Management of Neurodegenerative Diseases.

Oxidative catabolism of monoamine neurotransmitters by monoamine oxidases (MAOs) produces reactive oxygen species (ROS), which contributes to neuronal cells' death and also lowers monoamine neurotransmitter levels. In addition, acetylcholinesterase activity and neuroinflammation are involved in neurodegenerative diseases. Herein, we aim to achieve a multifunctional agent that inhibits the oxidative catabolism of monoamine neurotransmitters and, hence, the detrimental production of ROS while enhancing neurotransmitter levels. Such a multifunctional agent might also inhibit acetylcholinesterase and neuroinflammation. To meet this end goal, a series of aminoalkyl derivatives of analogs of the natural product hispidol were designed, synthesized, and evaluated against both monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B). Promising MAO inhibitors were further checked for the inhibition of acetylcholinesterase and neuroinflammation. Among them, compounds 3aa and 3bc were identified as potential multifunctional molecules eliciting submicromolar selective MAO-B inhibition, low-micromolar AChE inhibition, and the inhibition of microglial PGE2 production. An evaluation of their effects on memory and cognitive impairments using a passive avoidance test confirmed the in vivo activity of compound 3bc, which showed comparable activity to donepezil. In silico molecular docking provided insights into the MAO and acetylcholinesterase inhibitory activities of compounds 3aa and 3bc. These findings suggest compound 3bc as a potential lead for the further development of agents against neurodegenerative diseases.

Synthesis and antimicrobial activity of knipholone analogs

In the present study, we use knipholone as a prototype molecule to identify new anti-infective agents. Since knipholone is insoluble in water, which would have a detrimental effect on its bioavailability and efficacy, we synthesized knipholone Mannich base derivatives (2–4) that have better predicted solubility and investigated their in vitro antimicrobial activity against eight pathogenic bacterial and fungal strains. The chemical structures of compounds 1–4 were elucidated from their 1H and 13C NMR data, and their antimicrobial activity evaluation was carried out by a broth microdilution MTT assay. Compound 3 exhibited the strongest efficacy against Staphylococcus epidermidis, with MIC value of 9.7 µg/mL. While 4 exhibited the best activity against Staphylococcus aureus, with an MIC value of 19.5 µg/mL, and was the only one to significantly inhibit the fungus Trichophyton mentagrophytes (MIC = 78.2 µg/mL). The study provides evidence for the antibacterial activity of aminoalkyl derivatives of knipholone.

Porous Polymeric Membranes Doped with Halloysite Nanotubes and Oxygenic Polyoxometalates

AbstractEndowing anti‐fouling capabilities to water treatment membranes is a key feature for their long lifetime, but it continues to be a challenging task. Herein, a strategy for preparing composite membranes is reported comprising halloysite nanotubes (HNTs) as scaffolds to support a ruthenium substituted polyoxometalate (Ru4POM), with the goal of using evolved O2, resulting from the Ru4POM‐catalyzed H2O2 dismutation, as anti‐fouling agent. Two different amino alkyl derivatives, that is, a phosphonate and a silane, are grafted, respectively, in the lumen and on the surface of HNTs to support Ru4POM, and the resulting hybrid nanostructures are compared, in terms of catalytic efficiency and stability, to establish the most promising membrane additive. Porous polyether sulfone–based membranes are thus prepared to obtain a first proof of concept for this doping strategy. With respect to the former Ru4POM‐containing membranes, HNTs provide Earth‐abundant and low‐cost scaffolds for their efficient dispersion in the polymeric matrix. Preliminary tests on permeability and anti‐fouling behavior are finally discussed.

Synthesis and antiproliferative activities of polymethoxyflavones aminoalkyl and amino acid derivatives

Abstract Twelve novel aminoalkyl derivatives 3a-3f, 4a-4f and four novel amino acid derivatives 5a, 5b, 6a and 6b of polymethoxyflavones 1 and 2 were synthesized through regioselective demethylation, etherification, amination, EDCl-mediated amide condensation and alkaline hydrolysis, using tangeretin and nobiletin as starting materials. Their antiproliferative activities against four different human cancer cell lines (Aspc-1, SUN5, HepG-2 and HCT116) were evaluated by in vitro CCK-8 assay. The results show that the majority of the synthetic compounds exhibited moderate to good antiproliferative activity. In particular, the antiproliferative activity of compound 5b against HepG-2 cells (IC50 0.057 μM) was equal to the positive control drug Staurosporine (IC50 0.0575 μM).

Synthesis and Aminoalkylation of N-Propargyl Triterpene Aldimines

Mannich reaction of N-propargyl triterpene aldimines obtained from betulonic and oleanonic aldehydes gave new aminoalkyl derivatives containing an N-methylpiperazine fragment.

Biological properties and structural study of new aminoalkyl derivatives of benzimidazole and benzotriazole, dual inhibitors of CK2 and PIM1 kinases

The new aminoalkyl-substituted derivatives of known CK2 inhibitors 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi) and 4,5,6,7-tetrabromo-1H-benzotriazole (TBBt) were synthesized, and their influence on the activity of recombinant human CK2 α, CK2 holoenzyme and PIM1 kinases was evaluated. All derivatives inhibited the activity of studied kinases and the most efficient were aminopropyl-derivatives 8b and 14b. These compounds also exerted inhibition of cancer cell lines – CCRF-CEM (acute lymphoblastoid leukemia), MCF-7 (human breast cancer), and PC-3 (prostate cancer) proliferation and their EC50 is comparable with the value for clinically studied CK2 inhibitor CX-4945. Preliminary structure activity relationship analysis indicated that the spacer length affected antitumor potency, and two to three methylene units were more favorable. The complex of CK2 α1-335/8b was crystallized, both under high-salt conditions and under low-salt conditions giving crystals which diffracted X-rays to about 2.4 Å resolution, what enabled the determination of the corresponding 3D-structures.

Chlorophenoxy aminoalkyl derivatives as histamine H3R ligands and antiseizure agents

A series of twenty new chlorophenoxyalkylamine derivatives (9–28) was synthesized and evaluated on their binding properties at the human histamine H3 receptor (hH3R). The spacer alkyl chain contained five to seven carbon atoms. The highest affinities have shown the 4-chloro substituted derivatives 10 and 25 (Ki=133 and 128nM, respectively) classified as antagonists in cAMP accumulation assay (EC50=72 and 75nM, respectively). Synthesized compounds were also evaluated for anticonvulsant activity in Antiepileptic Screening Program (ASP) at National Institute of Neurological Disorders and Stroke (USA). Two compounds (4-chloro substituted derivatives: 20 and 26) were the most promising and showed in the MES seizure model in rats (after ip administration) ED50 values of 14mg/kg and 13.18mg/kg, respectively. Protective indexes (PI=TD50/ED50) were 3.2 for 20 and 3.8 for 26. Moreover, molecular modeling and docking studies were undertaken to explain affinity at hH3R of target compounds, and the experimentally and in silico estimation of properties like lipophilicity and metabolism was performed. Antiproliferative effects have been also investigated in vitro for selected compounds (10 and 25). These compounds neither possessed significant antiproliferative and antitumor activity, nor modulated CYP3A4 activity up to concentration of 10μM.

Preparation and characterization of nanoparticles made from amphiphilic mono and per-aminoalkyl-β-cyclodextrins

Abstract Aminoalkyl derivatives of β-cyclodextrin, in their neutral form are insoluble amphiphilic cyclodextrins that could be dispersed as nanoparticles in water. Such nanoparticles solubilize host molecules either in the non-polar medium in between the alkyl chains or in an environment of medium polarity inside the hydrophobic cavity of the cyclodextrins. This allows the solubilization of a wider range of molecules such as drugs, fragrances, aromas… than classical nanoparticles containing either oil or polymer. A series of such compounds either mono- or per-substituted at the C6 methylene of the β-CD primary rim with either short butyl chain or long dodecyl chain are obtained by chemical modification of native β-cyclodextrin with aminoalkyl groups. Their physicochemical properties and utilization for the manufacture of nanoparticles have been studied. The solubility assessed from direct microscopy observation and surface tension measurements were low; they were related to the hydrophobic character of the amphiphilic β-CDs, that is, the number and length of their alkyl chains. The monobutyl derivative adsorbs at the air–water interface as a monolayer whereas the most hydrophobic derivatives collapses into a 3-dimensional adsorbed layer. Stable nanoparticles were prepared by means of dispersion by ultrasound or by the nanoprecipitation method. Sonication yielded large and polydisperse nanoparticles of size larger than 500 nm; nanoprecipitation resulted in the formation of small nanoparticles with sizes in the range 100–200 nm with a narrow particle size distributions.

Novel Potent and Selective Acetylcholinesterase Inhibitors as Potential Drugs for the Treatment of Alzheimer's Disease: Synthesis, Pharmacological Evaluation, and Molecular Modeling of Amino-Alkyl-Substituted Fluoro-Chalcones Derivatives.

A new series of-fluoro chalcones-substituted amino-alkyl derivatives (3a˜3l) were designed, synthesized, characterized and evaluated for the inhibitory activity against acetylcholinesterase and butyrylcholinesterase. The results showed that the alteration of fluorine atom position and amino-alkyl groups markedly influenced the activity and the selectivity of chalcone derivates in inhibiting acetylcholinesterase and butyrylcholinesterase. Among them, compound 3l possesses the most potent inhibitory against acetylcholinesterase (IC50 =0.21±0.03μmol/L), and the highest selectivity for acetylcholinesterase over butyrylcholinesterase (IC50 (BuChE)/IC50 (AChE)=65.0). Molecular modeling and enzyme kinetic study on compound 3l supported its dual acetylcholinesterase inhibitory profile, simultaneously binding at the catalytic active and peripheral anionic site of the enzyme.

Magnesium Sulfate Promoted Efficient and Green Synthesis of Aminoalkyl, Amidoalkyl and Diarylmethane Derivatives

Magnesium Sulfate Promoted Efficient and Green Synthesis of Aminoalkyl, Amidoalkyl and Diarylmethane Derivatives

Aminoalkyl Derivatives of Guanidine Diaromatic Minor Groove Binders with Antiprotozoal Activity

Considering the strong DNA minor groove binding observed for our previous series of diaromatic symmetric and asymmetric guanidinium and 2-aminoimidazolinium derivatives, we report now the synthesis of new aminoalkyl derivatives of diaromatic guanidines with potential as DNA minor groove binders and antiprotozoal activity. The preparation of these aminoalkyl derivatives (12a-e, 13a-e, 14a-c,e, 15a-e, 16a-e) is presented as well as their affinity for DNA which was evaluated by means of DNA thermal denaturation experiments. Finally, the antiprotozoal activity of most of these aminoalkyl minor groove binders was evaluated in vitro against Trypanosoma brucei rhodesiense (8 compounds) and Plasmodium falciparum (18 compounds). The O-linked derivatives 13c and 14c showed 100 nM activities against P. falciparum, whereas for T. b. rhodesiense all compounds tested showed micromolar activity. Some of the derivatives prepared seem to exert the antimalarial activity by binding to the DNA minor groove whereas other sets of compounds could exert this antimalarial activity by inhibiting the parasite dihydrofolate reductase, for example.

Phosphonomethylation of Dinitroaniline-Substituted Alkylamines

It was found that aminoalkyl derivatives of 2,4-dinitroaniline can be phosphonomethylated at the terminal aliphatic amino group using a known method, whereas the aromatic part of the molecule and bound nitrogen atom remain unaffected.

In vitro anticancer activity and evaluation of DNA duplex binding affinity of phenyl-substituted indoloquinolines

Phenyl-substituted indoloquinolines were studied for their biological activity and their DNA binding affinity. Water-soluble aminoalkyl derivatives were prepared and have shown significant in vitro anticancer activity. Unlike previous reports on the potential role of duplex DNA as target for various indoloquinoline based drugs, duplex UV melting experiments and fluorescence titrations suggest only weak and moderately strong binding of the phenyl-substituted indoloquinolines at 120 mM and 20 mM Na(+) concentrations, respectively. Binding is suggested by ethidium displacement and circular dichroism experiments to be associated with drug intercalation between base pairs.

Unexpected α,β-unsaturated products of reductive amination of the macrolide antibiotic josamycin

Reductive amination of the macrolide antibiotic josamycin with alkyl amines, using three different reducing agents: NaBH 3CN, NaBH 4 and NaBH(OAc) 3, yields surprisingly different major products which are identified as either Lewis complexes, aminoalkyl derivatives or α,β-unsaturated derivatives of josamycin by 1H and 13C NMR, FT-IR and ESI MS methods.

Umbelliferone aminoalkyl derivatives as inhibitors of human oxidosqualene-lanosterol cyclase

Human and murine lanosterol synthases (EC 5.4.99.7) were studied as targets of a series of umbelliferone aminoalkyl derivatives previously tested as inhibitors of oxidosqualene cyclases from other eukaryotes. Tests were carried out on cell cultures of human keratinocytes and mouse 3T3 fibroblasts incubated with radiolabeled acetate, and on homogenates prepared from yeast cells expressing human lanosterol synthase, incubated with radiolabeled oxidosqualene. In cell cultures of both human keratinocytes and mouse 3T3 fibroblasts, the observed inhibition of cholesterol biosynthesis was selective for oxidosqualene cyclase. The most active compounds bear an allylmethylamino chain in position-7 of the coumarin ring. The inhibition was critically dependent on the position and length of the inhibitor side chain, as well as on the type of aminoalkyl group inserted at the end of the same chain. Molecular docking analyses, carried out to clarify details of inhibitors/enzyme interactions, proved useful to explain the observed differences in inhibitory activities.

Naphtho[2,3-f]indole-5,10-dione aminoalkyl derivatives: A new class of topoisomerase I inhibitors

Naphtho[2,3-f]indole-5,10-dione aminoalkyl derivatives in cytotoxic concentrations inhibit topoisomerase I, which is an important factor of antitumor activity of compounds of this chemical class. The degree of topoisomerase I inhibition with naphtho[2,3-f]indole-5,10-dione derivatives depends on the structure and position of active (aminoalkyl) groups. The mechanism of topoisomerase I inhibition with aminoalkylnaph-tho[2,3-f]indole-5,10-diones differs from specific blocking of the catalytic activity of the enzyme and depends on interactions of these compounds with DNA.

1H-Pyrazolo[3,4-g]hexahydro-isoquinolines as selective glucocorticoid receptor antagonists with high functional activity

Addition of the 4-fluorophenylpyrazole group to the previously described 2-azadecalin glucocorticoid receptor (GR) antagonist 1 resulted in significantly enhanced functional activity. SAR of the bridgehead substituent indicated that whereas groups as small as methyl afforded high GR binding, GR functional activity was enhanced by larger groups such as benzyl, substituted ethers, and aminoalkyl derivatives. GR antagonists with binding and functional activity comparable to mifepristone were discovered (e.g., 52: GR binding K(i) 0.7 nM; GR reporter gene functional K(i) 0.6 nM) and found to be highly selective over other steroid receptors. Analogues 43 and 45 had >50% oral bioavailability in the dog.

Modular syntheses of oxazolinylamine ligands and characterization of group 10 metal complexes

The syntheses of aminoalkyloxazoline and pyrrolidinyloxazoline ligands, each of which bear a pair of chiral centres, by both known and new routes are reported. Variable temperature NMR studies show that the known stepwise syntheses of the pyrrolidinyl compounds are not complicated by epimerization; however, coordination of one of the aminoalkyl derivatives to Pt(II) under conditions of prolonged heating to 80 °C does give mixtures of diastereomeric N,N ′-chelated complexes that result from inversion of the chiral centre associated with the aminoalkyl fragment. A new synthesis of pyrrolidinyloxazoline ligands that involves the Zn-catalyzed cyclization of Cbz-protected 2-cyanopyrrolidine and β-amino alcohols is also reported. This procedure offers the advantages of economy, shorter time, and fewer purification steps over the previously reported synthesis. In addition, the crystal structure of an enantiopure Pd(II) complex of an N,N ′-chelated pyrrolidinyloxazoline is disclosed. This compound has a pseudo-C2 axis of symmetry, which may make it suitable for asymmetric catalytic applications.Key words: chiral ligands, ligand design, oxazolines, variable temperature NMR spectroscopy, asymmetric catalysis, coordination compounds, palladium, platinum

Effect of substituents on diarylmethanes for antitubercular activity

Aminoalkyl derivatives of diarylmethanes were prepared using Grignard, Friedel–Crafts arylation and aminohydrochloride chain formation reactions. These series of compounds were evaluated against Mycobacterium tuberculosis H 37R v and showed the activity in the range of 6.25–25 μg/mL. Effect of heteroaryl, anthracenyl and phenanthrene groups on diarylmethane pharmacophores for antitubercular activity is described.

Search for Cyclodextrin-Based Inhibitors of Anthrax Toxins: Synthesis, Structural Features, and Relative Activities

Recently, using structure-inspired drug design, we demonstrated that aminoalkyl derivatives of beta-cyclodextrin inhibited anthrax lethal toxin action by blocking the transmembrane pore formed by the protective antigen (PA) subunit of the toxin. In the present study, we evaluate a series of new beta-cyclodextrin derivatives with the goal of identifying potent inhibitors of anthrax toxins. Newly synthesized hepta-6-thioaminoalkyl and hepta-6-thioguanidinoalkyl derivatives of beta-cyclodextrin with alkyl spacers of various lengths were tested for the ability to inhibit cytotoxicity of lethal toxin in cells as well as to block ion conductance through PA channels reconstituted in planar bilayer lipid membranes. Most of the tested derivatives were protective against anthrax lethal toxin action at low or submicromolar concentrations. They also blocked ion conductance through PA channels at concentrations as low as 0.1 nM. The activities of the derivatives in both cell protection and channel blocking were found to depend on the length and chemical nature of the substituent groups. One of the compounds was also shown to block the edema toxin activity. It is hoped that these results will help to identify a new class of drugs for anthrax treatment, i.e., drugs that block the pathway for toxin translocation into the cytosol, the PA channel.