Novel propargylamine-based inhibitors of cholinesterases and monoamine oxidases: Synthesis, biological evaluation and docking study.

A combination of several pharmacophores in one molecule has been successfully used for multi-target-directed ligands (MTDL) design. New propargylamine substituted derivatives combined with salicylic and cinnamic scaffolds were designed and synthesized as potential cholinesterases and monoamine oxidases (MAOs) inhibitors. They were evaluated invitro for inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE) using Ellman's method. All the compounds act as dual inhibitors. Most of the derivatives are stronger inhibitors of AChE, the best activity showed 5-bromo-N-(prop-2-yn-1-yl)salicylamide 1e (IC50 = 8.05 µM). Carbamates (4-bromo-2-[(prop-2-yn-1-yl)carbamoyl]phenyl ethyl(methyl)carbamate 2d and 2,4-dibromo-6-[(prop-2-yn-1-yl)carbamoyl]phenyl ethyl(methyl)carbamate 2e were selective and the most active for BuChE (25.10 and 26.09 µM). 4-Bromo-2-[(prop-2-yn-1-ylimino)methyl]phenol 4a was the most potent inhibitor of MAOs (IC50 of 3.95 and ≈10 µM for MAO-B and MAO-A, respectively) along with a balanced inhibition of both cholinesterases being a real MTDL. The mechanism of action was proposed, and binding modes of the hits were studied by molecular docking on human enzymes. Some of the derivatives also exhibited antioxidant properties. Insilico prediction of physicochemical parameters affirm that the molecules would be active after oral administration and able to reach brain tissue.

Synthesis of propargylamine mycophenolate analogues and their selective cytotoxic activity towards neuroblastoma SH-SY5Y cell line.

Twenty six propargylamine mycophenolate analogues were designed and synthesized from mycophenolic acid 1 employing a key step A3-coupling reaction. Their cytotoxic activity was examined against six cancer cell lines. Compounds 6a, 6j, 6t, 6u, and 6z exhibited selective cytotoxicity towards neuroblastoma (SH-SY5Y) cancer cells and were less toxic to normal cells in comparison to the lead compound, MPA 1 and a standard drug, ellipticine. Molecular docking results suggested that compound 6a is fit well in the key amino acid of three proteins (CDK9, EGFR, and VEGFR-2) as targets in cancer therapy. The propargylamine mycophenolate scaffold might be a valuable starting point for development of new neuroblastoma anticancer drugs.

Immobilized Ag NPs on chitosan-biguanidine coated magnetic nanoparticles for synthesis of propargylamines and treatment of human lung cancer.

The magnetically isolable nanobiocomposites have significant impact as the modified new generation catalysts in recent days. This has persuaded us to design and synthesis of a novel Ag NPs decorated biguanidine-chitosan (Bigua-CS) dual biomolecular functionalized core-shell type magnetic nanocomposite (Ag/Bigua-CS@Fe3O4). Bigua-CS could be introducing polysaccharide materials as potential coating agent to immobilizing and stabilizing metal nanoparticles. The material was characterized using several advanced techniques like fourier transformed infrared spectroscopy (FT-IR), inductively coupled plasma (ICP), field emission scanning electron microscopy (FE-SEM), energy dispersive X-ray spectroscopy (EDX), atomic mapping, high resolution transmission electron microscopy (HR-TEM), vibrating sample magnetometer (VSM) and X-ray diffraction (XRD). Towards the chemical applications of the material, we headed the multicomponent synthesis of diverse propargylamines by A3 coupling in water, which ended up with excellent yields. Due to strong paramagnetism, the catalyst was easily isolable and reused in 9cycles without any leaching and considerable change in reactivity. In addition, the catalyst was engaged in biological assays like study of anti-oxidant properties by DPPH mediated free radical scavenging test using BHT as a reference molecule. Thereafter, on having a significant IC50 value in radical scavenging assay, we extended the bio-application of the catalyst in anticancer study of adenocarcinoma cells of human lungs. The three different cancer cell lines, PC-14, LC-2/ad and HLC-1 were used in this regard. The best result was achieved in the case of PC-14 cell line with strong IC50 values.

Direct Conversion of N-Alkylamines to N-Propargylamines through C-H Activation Promoted by Lewis Acid/Organocopper Catalysis: Application to Late-Stage Functionalization of Bioactive Molecules.

An efficient catalytic method to convert an α-C-H bond of N-alkylamines into an α-C-alkynyl bond was developed. In the past, such transformations were carried out under oxidative conditions, and the enantioselective variants were confined to tetrahydroisoquinoline derivatives. Here, we disclose a method for the union of N-alkylamines and trimethylsilyl alkynes, without the presence of an external oxidant and promoted through cooperative actions of two Lewis acids, B(C6F5)3 and a Cu-based complex. A variety of propargylamines can be synthesized in high diastereo- and enantioselectivity. The utility of the approach is demonstrated by the late-stage site-selective modification of bioactive amines. Kinetic investigations that shed light on various mechanistic nuances of the catalytic process are presented.

One-pot synthesis of propargylamines using magnetic mesoporous polymelamine formaldehyde/zinc oxide nanocomposite as highly efficient, eco-friendly and durable nanocatalyst: optimization by DOE approach.

Magnetic mesoporous polymelamine formaldehyde nanocomposite-incorporating ZnO nanoparticles were successfully synthesized using solvothermal and sol-gel methods. Fourier-transform infrared spectrometry (FT-IR), X-ray diffraction, Brunauer-Emmett-Teller, vibrating sample magnetometer, thermogravimetric analysis, elemental analysis, transmission electron microscopy and field emission scanning electron microscopy techniques were then utilized for evaluation of nanocomposites. The as-prepared nanocomposite can be used as heterogeneous nanocatalyst with remarkable performance for A3 coupling reaction toward one-pot synthesis of propargylamine and its derivatives under solvent-less condition. In order to maximize the product yield, the variables, i.e., reaction time, temperature and catalyst amount, were optimized by using a statistical approach. The synthesized nanocomposite can be easily separated from the reaction medium and reused over and over, without significant changes in its catalytic activity.

Evaluation of drug candidature: In silico ADMET, binding interactions with CDK7 and normal cell line studies of potentially anti-breast cancer enamidines.

We have recently explored novel class of potentially anti-breast cancer active enamidines in which four molecules 4a-c and 4h showed higher anticancer activity compared to standard drug doxorubicin. As a part of extension of this work, we have further evaluated in silico cheminformatic studies on bioactivity prediction of synthesized series of enamidines using mole information. The normal cell line study of four lead compounds 4a-c and 4h against African green monkey kidney vero strain further revealed that the compounds complemented good selectivity in inhibition of cancer cells. The in silico bioactivity and molecular docking studies also revealed that the compounds have significant interactions with the drug targets. The results reveal that enamidine moieties are vital for anti-breast cancer activity as they possess excellent drug-like characteristics, being potentially good inhibitors of cyclin dependent kinases7 (CDK7).

A fragment-like approach to PYCR1 inhibition.

Pyrroline-5-carboxylate reductase 1 (PYCR1) is the final enzyme involved in the biosynthesis of proline and has been found to be upregulated in various forms of cancer. Due to the role of proline in maintaining the redox balance of cells and preventing apoptosis, PYCR1 is emerging as an attractive oncology target. Previous PYCR1 knockout studies led to a reduction in tumor growth. Accordingly, a small molecule inhibitor of PYCR1 could lead to new treatments for cancer, and a focused screening effort identified pargyline as a fragment-like hit. We report the design and synthesis of the first tool compounds as PYCR1 inhibitors, derived from pargyline, which were assayed to assess their ability to attenuate the production of proline. Structural activity studies have revealed the key determinants of activity, with the most potent compound (4) showing improved activity in vitro in enzyme (IC50 = 8.8 µM) and pathway relevant effects in cell-based assays.

Ternary hybrid TiO2-PANI-AuNPs for photocatalytic A3-coupling of aldehydes, amines and alkynes: First photochemical synthesis of propargyl amines.

The present paper describes the successful synthesis and application of a ternary hybrid consists of gold nanoparticles decorated on titania-polyaniline (TiO2-PANI-AuNPs) for A3-coupling between aldehydes, terminal alkynes and amines under visible irradiation. The synthesis of ternary hybrid involved the coating of PANI on TiO2 via an oxidative polymerization method followed by the deposition of AuNPs on TiO2-PANI using trisodium citrate as a reducing agent. The synthesized photocatalyst was characterized by various techniques like FT-IR, SEM, HR-TEM, XRD, UV-VIS, ICP-AES, TGA, XPS and PL spectroscopy. The synthesized photocatalyst exhibited higher efficiency which was presumed due to the suppressed electron-hole recombination and better electron mobility at the surface of the photocatalyst. In the hybrid, polyaniline was found to enhance the activity as well as stability of the photocatalyst owing to its chemical interaction with titania and gold. Furthermore, after the reaction, the photocatalyst could readily be recovered and recycled for several runs with consistent photoactivity.

Design, synthesis and evaluation of pentacycloundecane and hexacycloundecane propargylamine derivatives as multifunctional neuroprotective agents.

The multifactorial pathophysiology of neurodegenerative disorders remains one of the main challenges in the design of a single molecule that may ultimately prevent the progression of these disorders in affected patients. In this article, we report on twelve novel polycyclic amine cage derivatives, synthesized with or without a propargylamine function, designed to possess inherent multifunctional neuroprotective activity. The MTT cytotoxicity assay results showed the SH-SY5Y human neuroblastoma cells to be viable with the twelve compounds, particularly at concentrations less than 10 µM. The compounds also showed significant neuroprotective activity, ranging from 31% to 61% at 1 µM, when assayed on SH-SY5Y human neuroblastoma cells in which neurodegeneration was induced by MPP+. Calcium regulation assays conducted on the same cell line showed the compounds to be significant VGCC blockers with activity ranging from 26.6% to 51.3% at 10 µM; as well as significant NMDAr antagonists with compound 5 showing the best activity of 88.3% at 10 µM. When assayed on human MAO isoenzymes, most of the compounds showed significant inhibitory activity, with compound 5 showing the best activity (MAO-B: IC50 = 1.70 µM). Generally, the compounds were about 3-52 times more selective to the MAO-B isoenzyme than the MAO-A isoenzyme. Based on the time-dependency studies conducted, the compounds can be defined as reversible MAO inhibitors. Several structure activity relationships were derived from the various assays conducted, and the compounds' possible putative binding modes within the MAO-B enzyme cavity were assessed in silico.

Immobilized Gold Nanoparticles Prepared from Gold(III)-Containing Ionic Liquids on Silica: Application to the Sustainable Synthesis of Propargylamines.

A cycloaurated phosphinothioic amide gold(III) complex was supported on amorphous silica with the aid of an imidazolium ionic liquid (IL) physisorbed in the SiO2 pores (SiO2⁻IL) and covalently bonded to the SiO2 (SiO2@IL). Gold(0) nanoparticles (AuNPs) were formed in situ and subsequently immobilized on the SiO2⁻IL/SiO2@IL phase. The resulting catalytic systems Au⁻SiO2⁻IL and Au⁻SiO2@IL promoted the solvent-free A³ coupling reaction of alkynes, aldehydes, and amines in high yields under solvent-free conditions with very low catalyst loading and without the use of additives. The Au⁻SiO2@IL catalyst showed good recyclability and could be reused at least five times with yields of propargylamines of ≥80%. This synthetic method provides a green and low cost way to effectively prepare propargylamines. Additionally, 31P high resolution magic angle spinning (HRMAS) NMR spectroscopy is introduced as a simple technique to establish the Au loading of the catalyst.

Structure-Activity Relationship of Propargylamine-Based HDAC Inhibitors.

As histone deacetylases (HDACs) play an important role in the treatment of cancer, their selective inhibition has been the subject of various studies. These continuous investigations have given rise to a large collection of pan- and selective HDAC inhibitors, containing diverse US Food and Drug Administration (FDA)-approved representatives. In previous studies, a class of alkyne-based HDAC inhibitors was presented. We modified this scaffold in two previously neglected regions and compared their cytotoxicity and affinity toward HDAC1, HDAC6, and HDAC8. We were able to show that R-configured propargylamines contribute to increased selectivity for HDAC6. Docking studies on available HDAC crystal structures were carried out to rationalize the observed selectivity of the compounds. Substitution of the aromatic portion by a thiophene derivative results in high affinity and low cytotoxicity, indicating an improved drug tolerance.

Alkyne Ligation Handles: Propargylation of Hydroxyl, Sulfhydryl, Amino, and Carboxyl Groups via the Nicholas Reaction.

The Nicholas reaction has been applied to the installation of alkyne ligation handles. Acid-promoted propargylation of hydroxyl, sulfhydryl, amino, and carboxyl groups using dicobalt hexacarbonyl-stabilized propargylium ions is reported. This method is useful for introduction of propargyl groups into base-sensitive molecules, thereby expanding the toolbox of methods for the incorporation of alkynes for bio-orthogonal reactions. High-value molecules are used as the limiting reagent, and various propargylium ion precursors are compared.

Synthesis of Chiral Fluorinated Propargylamines via Chemoselective Biomimetic Hydrogenation.

A highly enantioselective synthesis of chiral fluorinated propargylamines was developed through phosphoric acid and ruthenium-catalyzed chemoselective biomimetic hydrogenation of the carbon-nitrogen double bond of fluorinated alkynyl ketimines in the presence of a carbon-carbon triple bond. This reaction features high chemoselectivity and slow background reaction. In addition, selective transformations of the chiral fluorinated propargylamines were also reported.

Design, synthesis and biological evaluation of N-methyl-N-[(1,2,3-triazol-4-yl)alkyl]propargylamines as novel monoamine oxidase B inhibitors.

Different azides and alkynes have been coupled via Cu-catalyzed 1,3-dipolar Huisgen cycloaddition to afford a novel family of N1- and C5-substituted 1,2,3-triazole derivatives that feature the propargylamine group typical of irreversible MAO-B inhibitors at the C4-side chain of the triazole ring. All the synthesized compounds were evaluated against human MAO-A and MAO-B. Structure-activity relationships and molecular modeling were utilized to gain insight into the structural and chemical features that enhance the binding affinity and selectivity between the two enzyme isoforms. Several lead compounds, in terms of potency (submicromolar to low micromolar range), MAO-B selective recognition, and brain permeability, were identified. One of these leads (MAO-B IC50 of 3.54µM, selectivity MAO-A/MAO-B index of 27.7) was further subjected to reversibility and time-dependence inhibition studies, which disclosed a slow and irreversible inhibition of human MAO-B. Overall, the results support the suitability of the 4-triazolylalkyl propargylamine scaffold for exploring the design of multipotent anti-Alzheimer compounds endowed with irreversible MAO-B inhibitory activity.

Synthesis and biological evaluation of novel propargylquinobenzothiazines and their derivatives as potential antiproliferative, anti-inflammatory, and anticancer agents.

Azaphenothiazines containing the quinoline ring, 8-10-substituted 6H-quinobenzothiazines and 6H-diquinothiazine were transformed into new 6-propargyl and 6-dialkylaminobutynyl derivatives containing the triple bond. Most of them displayed strong antiproliferative actions against human peripheral blood mononuclear cells (PBMC) stimulated with phytohemagglutinin A (PHA), strongly suppressed lipopolysaccharide (LPS)-induced TNF-α production by whole blood human cell cultures, and exhibited low cytotoxicity. Three propargylquinobenzothiazines with the bromine, trifluoromethyl, and methylthio groups at position 9 and propargyldiquinothiazine exhibited comparable actions to cisplatin against the L-1210 and SW-948 tumor lines. 6-Propargyl-9-trifluoromethylquinobenzothiazine was shown to block caspase 3 expression and inhibit expression of caspase 8 and 9 in Jurkat cells indicating its possible mechanism of action. These derivatives could be promising, potential therapeutics for treatment of neoplastic diseases and autoimmune disorders.

C-Propargylation Overrides O-Propargylation in Reactions of Propargyl Chloride with Primary Alcohols: Rhodium-Catalyzed Transfer Hydrogenation.

The canonical SN 2 behavior displayed by alcohols and activated alkyl halides in basic media (O-alkylation) is superseded by a pathway leading to carbinol C-alkylation under the conditions of rhodium-catalyzed transfer hydrogenation. Racemic and asymmetric propargylations are described.

Enantioselective alkynylation of benzo[e][1,2,3]-oxathiazine 2,2-dioxides catalysed by (R)-VAPOL-Zn complexes: synthesis of chiral propargylic cyclic sulfamidates.

(R)-VAPOL-Zn(II) complexes catalysed the enantioselective addition of terminal alkynes to cyclic benzoxathiazine 2,2-dioxides, providing the corresponding chiral propargylic sulfamidates with high yields (up to 93%) and good enantiomeric excesses (up to 87%).

Copper-catalyzed trifluoromethylalkynylation of isocyanides.

The title reaction proceeds with acetylenic triflones and isocyanides under mild conditions using copper as a catalyst. This transformation provides an efficient access to (E)-N-alkyl trifluoromethyl alkynyl ketoimines, which are useful building blocks for the synthesis of CF3-containing N-heterocycles, propargylamines, etc.

Cp2TiCl2-catalyzed cis-hydroalumination of propargylic amines with Red-Al: stereoselective synthesis of Z-configured allylic amines.

A titanium-catalyzed cis-hydroalumination of propargylic amines with Red-Al is described, which provides an efficient way to produce Z-configured allylic amines in good to excellent yields with high stereoselectivity and good regioselectivity. The hydride-bridged Al/Ti bimetallic species may act as a real catalyst in this reaction.

Novel arylalkenylpropargylamines as neuroprotective, potent, and selective monoamine oxidase B inhibitors for the treatment of Parkinson's disease.

To develop novel neuroprotective agents, a library of novel arylalkenylpropargylamines was synthesized and tested for inhibitory activities against monoamine oxidases. From this, a number of highly potent and selective monoamine oxidase B inhibitors were identified. Selected compounds were also tested for neuroprotection in in vitro studies with PC-12 cells treated with 6-OHDA and rotenone, respectively. It was observed that some of the compounds tested yielded a marked increase in survival in PC-12 cells treated with the neurotoxins. This indicates that these propargylamines are able to confer protection against the effects of the toxins and may also be considered as novel disease-modifying anti-Parkinsonian agents, which are much needed for the therapy of Parkinson's disease.