Piperidinyl Moiety Research Articles

Developing new anticancer agents: Design, synthesis, biological evaluation and in silico study of several functionalized pyrimidine-5-carbonitriles as small molecules modulators targeting breast cancer

Committed to our growing effort addressed toward the development of potent anti-breast cancer candidates, new 4-hydrazinylpyrimidine-5-carbonitriles featuring a morpholinyl or piperidinyl moiety at the position-2 and derivatized with various functionalities at the hydrazinyl group were designed through structure optimization, and their antiproliferative potency against two human breast cancer (BC) cell lines, relative to the reference drug 5-FU, was evaluated. Compounds showing remarkable cytotoxic activity versus the hormone dependent MCF-7 cell line (IC50 = 1.62 ± 0.06 µM– 9.88 ± 0.38 µM) and the non-hormone dependent MDA-MB-231 cell line (IC50 = 3.26 ± 0.14 µM–12.93 ± 0.55 µM) were further tested by multiple assays for clarification of their potential activity. Promising derivatives revealing low damage to healthy cells were subject to enzymatic inhibitory assessment against ARO and EGFR and their activities compared to letrozole and erlotinib respectively. Compounds 3c, 6a as well as compounds 4c, 4d proved to be good inhibitors of the ARO and EGFR enzymes respectively. Active compounds were also evaluated for their underlying mode of action by further investigation for CDK, Hsp90, PI3K inhibition and compared to normal MCF-10A cells and assessed for their enhancement of the caspase 9 levels. Additionally, cell cycle analysis and apoptotic induction were performed. They demonstrated remarkable activities in the previous assays and emanated as leads as anti-breast cancer candidates. Eventually, molecular docking analysis revealed that hit compounds 3c, 4c, 4d, and 6a could bind favorably to the proposed in silico models of various protein–ligand interactions. Therefore, our promising top candidates, by demonstrating appreciable anti-breast cancer activities, present valuable prospects for optimization, potency enhancement and future application.

Discovery of 3-phenyl- and 3-N-piperidinyl-isothiazolo[4,3-b]pyridines as highly potent inhibitors of cyclin G-associated kinase.

Structural modifications at position 3 of the isothiazolo[4,3-b]pyridine scaffold afforded a new series of cyclin G-associated kinase (GAK) inhibitors. It was shown that the insertion of a carboxamide residue at position 3 of a phenyl or piperidinyl moiety generated potent GAK inhibitors with IC50 values in a low nanomolar range. This potent GAK binding affinity was rationalized by molecular modelling demonstrating that the carboxamide moiety engages in an extra hydrogen bond with GAK. Moreover, this new series of compounds was also endowed with antiviral activity against dengue virus, highlighting the potential utility of GAK as a target for the development of antiviral drugs.

Antiprotozoal Activity of Xanthone Derivatives

A series of xanthone derivatives containing different side chains, including ω-bromo and ω-aminoalkoxylxanthones (with linear alkoxy chains of 3, 4 and 5 carbon atoms and methyl, propyl, tert -butylamino and piperidinyl moieties), synthesized from the natural xanthone lichexanthone were tested for their antiprotozoal activities against Leishamania braziliensis , L. major and Trypanosoma cruzi (extra and intracellular forms). The ω-aminoalkoxylxanthones showed good antileishmanial activity, with IC 50 ranging from 62.8 to 0.1 µM for promastigotes and 119.3 to 2.4 µM for amastigotes. In general, compounds with longer alkyl chains and tert -butylamino moiety showed better activity. The cytotoxicity on VERO cells was also described for some derivatives. Compound 15 ( tert -butylaminobutyloxy side chain) was the most active on promastigote forms (IC 50 0.1 µM), compound 16 ( tert -butylaminopentyloxy side chain) sowed the best activity for amastigotes (IC 50 2.4 µM) and derivative 13 (dipropylaminopentyloxy side chain) was the most selective (selectivity index of 9.4). Regarding trypanocidal activity, 16 and other groups of derivatives, (ω-bromoalkoxylxanthones, prenyl and epoxyl side chains) had moderate to good activity on T. cruzi trypomastigotes, with IC 50 ranging from 30.6 to 4.1 µM, while only two ω-aminoalkoxylxanthones ( 10 and 11 ) were weakly active against T. cruzi amastigotes. DOI: http://dx.doi.org/10.17807/orbital.v12i3.1460

Synthesis and antibacterial evaluation of novel oxazolidinone derivatives containing a piperidinyl moiety.

In this article, a series of novel oxazolidinone derivatives containing a piperidinyl moiety was designed and synthesized. Their antibacterial activities were measured against S. aureus, MRSA, MSSA, LREF and VRE by MIC assay. Most of them exhibited potent activity against Gram-positive pathogens comparable to linezolid. Among them, compound 9h exhibited comparable activity with linezolid against human MAO-A for safety evaluation and showed moderate metabolism in human liver microsome. The most promising compound 9h, which showed remarkable antibacterial activity against S. aureus, MRSA, MSSA, LREF and VRE pathogens with MIC value of 0.25-1 μg/mL, was an interesting candidate for further investigation.

Optimization of P2Y12 Antagonist Ethyl 6-(4-((Benzylsulfonyl)carbamoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate (AZD1283) Led to the Discovery of an Oral Antiplatelet Agent with Improved Druglike Properties.

P2Y12 antagonists are widely used as antiplatelet agents for the prevention and treatment of arterial thrombosis. Based on the scaffold of a known P2Y12 antagonist AZD1283, a series of novel bicyclic pyridine derivatives were designed and synthesized. The cyclization of the ester substituent on the pyridine ring to the ortho-methyl group led to lactone analogues of AZD1283 that showed significantly enhanced metabolic stability in subsequent structure-pharmacokinetic relationship studies. The metabolic stability was further enhanced by adding a 4-methyl substituent to the piperidinyl moiety. Compound 58l displayed potent inhibition of platelet aggregation in vitro as well as antithrombotic efficacy in a rat ferric chloride model. Moreover, 58l showed a safety profile that was superior to what was observed for clopidogrel in a rat tail-bleeding model. These results support the further evaluation of compound 58l as a promising drug candidate.

Metabolism, Excretion and Pharmacokinetics of MLN3897, a CCR1 Antagonist, in Humans.

MLN3897 is a small molecule antagonist of the C-C chemokine receptor-1. Since preclinical studies showed that the molecule was metabolized into two halves, the metabolism, excretion, and pharmacokinetics of MLN3897 were investigated in humans using MLN3897 14C-radiolabeled either on the chlorophenyl (CP) or the tricyclic (TC) half of MLN3897 after an oral dose. To evaluate the mass balance, metabolism and pharmacokinetics of MLN3897 in two cohorts of six randomized healthy subjects. After receiving informed consent, subjects were dosed after an overnight fast of 10-hours followed by at least 4- hours after dosing on day-1. Each cohort received a single 29 mg oral dose of either the CP or the TC as an oral solution in water. Serial blood samples, urine and feces were collected over a 10-day period post-dose. For both radiolabeled moieties, 55-59% of the dose was recovered in feces and 32% recovered in urine. MLN3897 was metabolized extensively in humans, with minor amounts of intact MLN3897 detected in the urine and feces. N-oxidation of the tricyclic moiety (M28) and N-dealkylation of the piperidinyl moiety were the primary metabolic pathways leading to further formation of the carboxylic acid metabolite (M19) and the (4-(4-chlorophenyl)-3,3- dimethylpiperidin-4-ol) metabolite (M40). Oxidative metabolites M11, M19, M28, M44 were present at >10% of the total circulating radioactivity and also at >25% of MLN3897 exposure. Metabolites resulting from the chlorophenyl-labeled moiety (M40) had significantly more systemic exposure compared to the tricyclic-labeled moiety (M19).

Synthesis and SAR of thieno[3,2-b]pyridinyl urea derivatives as urotensin-II receptor antagonists

The preparation and SAR profile of thieno[3,2-b]pyridinyl urea derivatives as novel and potent urotensin-II receptor antagonists are described. An activity optimization study, probing the effects of substituents on thieno[3,2-b]pyridinyl core and benzyl group of the piperidinyl moiety, led to the identification of p-fluorobenzyl substituted thieno[3,2-b]pyridinyl urea 6n as a highly potent UT antagonist with an IC50 value of 13nM. Although 6n displays good metabolic stability and low hERG binding activity, it has an unacceptable oral bioavailability.

Novel silicon(IV) phthalocyanines containing piperidinyl moieties: Synthesis and in vitro antifungal photodynamic activities

A new series of silicon(IV) phthalocyanines (SiPcs) axially di-substituted with piperidinyl moieties (compounds 1, 2a, and 3a) and their N-methylated derivatives (compounds 2b and 3b) have been synthesized and characterized. Meanwhile, an analogue di-substituted with cyclohexyl groups (compound 4) has also been prepared as a control. The antifungal photoactivities of these SiPcs toward Candida albicans were found to follow the order: 2b ＞ 3a ≈ 3b ＞ 1 ≈ 2a ＞ 4. The structure–activity relationship of these phthalocyanines has been discussed by investigating their photophysical and photochemical properties, partition coefficient, and cellular uptake. The cationic phthalocyanine 2b shows the highest photodynamic activity against C. albicans causing 4 log10 reduction of this fungus at 100 μM, which could be attributed to its high singlet oxygen yields, less aggregation in aqueous media, and relatively efficient cellular uptake.

Stereoselective aminoxylation of biradical titanium enolates with TEMPO.

A highly efficient and straightforward aminoxylation of titanium(IV) enolates from (S)-N-acyl-4-benzyl-5,5-dimethyl-1,3-oxazolidin-2-ones with TEMPO has been developed. A wide array of functional groups on the acyl moiety, including alkyl and aryl substituents, olefins, esters, or α-cyclopropyl, as well as α-trifluoromethyl groups, are well tolerated. This transformation can therefore produce the α-aminoxylated adducts in excellent yields with high diastereomeric ratios (d.r.). In turn, parallel additions to the α,β-unsaturated N-acyl counterparts give the corresponding γ-adducts with complete regioselectivity in moderate to good yields. Removal of the piperidinyl moiety or the chiral auxiliary converts the resultant adducts into enantiomerically pure α-hydroxy carboxyl derivatives, alcohols, or esters in high yields under mild conditions. Finally, a new mechanistic model based on the biradical character of the titanium(IV) enolates has been proposed.

Increment of Antimycobaterial Activity on Lichexanthone Derivatives

A new dihydropyranexanthone derived from the natural xanthone lichexanthone (1) was synthesised and, together with other 18 derivatives including ω-bromo and ω-aminoalkoxylxanthones (containing methyl, ethyl, propyl, tertbutylamino and piperidinyl moieties), were tested against Mycobacterium tuberculosis. Nine ω-aminoalkoxylxanthones showed good antimycobacterial activity, and their in vitro cytotoxicity was determined using VERO cells in order to calculate the selectivity index (SI). One of these nitrogenated xanthone derivatives showed very promising results, with MIC of 2.6 μM and SI of 48. This MIC is comparable to values found in "first and second line" drugs commonly used to treat TB. In order to understand better about this compound, it was evaluated together with two other ones that showed good SI, against resistant clinical strains of M. tuberculosis to verify the existence of cross-resistance. A chemometrical approach was useful to establish a pattern of antitubercular activity among the group of ω-aminoalkoxylxanthones, according to some structural and chemical features.

Chiral Effect of a Phe Residue in Position 3 of the Dmt1-l(or d)-Tic2 Analogues on Opioid Functional Activities

In this letter, we describe a structure-activity relationships study, specifically related to the chirality of third amino acid residue in our H-Dmt-L(or D)-Tic analogues, of which C-terminus is attached to a piperidinyl moiety. Observed selectivities and functional activities of these analogues demonstrated that the chiralities of the second and third position residues are crucial for determining whether these ligands act as antagonists or agonists at the δ opioid receptor, but not at the μ opioid receptor.

Chemical modifications of a natural xanthone and antimicrobial activity against multidrug resistant Staphylococcus aureus and cytotoxicity against human tumor cell lines

A series of 15 ω-aminoalkoxylxanthones containing methyl, ethyl, propyl, tert-butylamino and piperidinyl moieties were synthesized from a natural xanthone isolated from a lichen species. These compounds were tested for their in vitro antibacterial properties against Gram-positive and Gram-negative bacteria and cytotoxicity against a number of human tumor cell lines was too evaluated. The newly synthesized derivatives revealed selective activity against Staphylococcus aureus (Gram-positive), and the most promising results are for a multidrug resistant strain, for which six of these compounds showed good activity (MICs 4 µg/mL). Many derivatives inhibited tumor cells growth and most compounds were active on multiple lines.

ChemInform Abstract: Solution‐Phase and Solid‐Phase Synthesis of Novel Transition State Inhibitors of Coagulation Enzymes Incorporating a Piperidinyl Moiety.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Solution-phase and solid-phase synthesis of novel transition state inhibitors of coagulation enzymes incorporating a piperidinyl moiety

2-Amino-3-piperidin-4-yl-propionic acid containing peptidomimetics are potent protease inhibitors when combined with an appropriate keto-thiazole or keto-carboxylic acid moiety. A novel P 1 residue in factor Xa and thrombin inhibitors has been found resulting in IC 50 values as low as 0.048 μM, a factor of ten more potent than Argatroban. Starting with non-chiral synthetic routes, a new stereospecific route was developed as well as a new solid-phase method.

Effect of lowered lipophilicity on the affinity of PCP analogues for the PCP receptor and the dopamine transporter

Summary Oxygen and sulphur atoms were introduced in the cyclohcxyl and piperidinyl moieties of the basic structures 1-(1-phenyl-cyclohexyl)piperidine (PCP), 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP), and 1-[1-(2-benzo[ b ]thiophenyl)cyclohexyl]piperidine (BTCP) to lower their global lipophilicity. The compounds obtained were tested comparatively for their affinity for the PCP receptor labelled with [ 3 H]TCP and for the dopamine (DA) transporter labelled with [ 3 H]BTCP. Lowering the global lipophilicity in PCP and TCP series is detrimental to the affinity and selectivity for the PCP receptor. In the BTCP series lowering of the global lipophilicity is less deleterious and may, on the contrary, be a useful way of increasing selectivity for the DA transporter in some instances.

Anti-idiotypes against an anti-haloperidol antibody bind to sigma receptors

Anti-idiotypic monoclonal antibodies that interact with the binding site of sigma receptors were generated. First, BALB/c mice were immunized with a haloperidol-bovine serum albumin conjugate, and monoclonal anti-haloperidol antibodies that recognize the piperidinyl moiety of haloperidol molecule were obtained. Second, for generation of anti-idiotypic antibodies, BALB/c mice were immunized with the anti-haloperidol monoclonal antibodies coupled to keyhole limpet hemocyanin. Anti-idiotypic antisera and three hybridomas secreting anti-idiotypic monoclonal antibodies were obtained. All of them were shown to inhibit [ 3H]haloperidol binding to the anti-haloperidol antibodies. The anti-idiotypes were potent in displacing the binding of [ 3H]haloperidol to rat brain sigma receptors. Furthermore, they significantly immunoprecipitated the sigma receptors from a detergent-solubilized preparation. These findings demonstrate the generation of anti-idiotypic monoclonal antibodies specifically interacting with membrane-bound and solubilized sigma receptors.

Synthesis and biodistribution of 99mTc-labeled piperidinyl bis(aminoethanethiol) complexes: potential brain perfusion imaging agents for single photon emission computed tomography.

In developing clinically useful 99mTc-labeled radiopharmaceuticals for the evaluation of regional cerebral perfusion with single photon emission computed tomography (SPECT), a number of substituted alkyl(aryl)piperidinyl bis(aminoethanethiol) ligands for chelating [99mTc]TcO(III) were synthesized. Each ligand forms two diastereomers, syn and anti, after reacting with a racemic mixture of the ligand. The diastereomers were separated by high-pressure liquid chromatography. In biodistribution studies conducted in rats, the diastereomers exhibit widely disparate brain uptake values; however, this disparity seems to diminish as the steric bulk of the substituent at the C-4 position of the piperidinyl moiety increases. Furthermore, all the complexes evaluated failed to show a prolonged retention in the rat brain, suggesting that further structural modification may be necessary to obtain clinically useful complexes from this class of compounds.

ChemInform Abstract: SYNTHESIS AND BIOLOGICAL PROPERTIES OF SOME SPIN‐LABELED 9‐AMINOACRIDINES

AbstractAus den 9‐Chlor‐acridinen (IV) werden durch Umsetzung mit den Spin‐markierten Aminen (I)‐(III) die 9‐Amino‐acridine (V) hergestellt.

Synthesis and biological properties of some spin-labeled 9-aminoacridines

Five spin-labeled 9-aminoacridines, each bearing either a 4-(2,2,6,6-tetramethyl-1-piperidinyloxy) or a 3-(2,2,5,5-tetramethyl-1-pyrrolidinyloxy) moiety in the 9 position, have been synthesized and assayed for biological activity in three different test systems. Sedimentation velocity measurements indicated that the labels caused unwinding of calf thymus DNA. Those acridines which contained both 6-chloro and 2-methoxy substituents were less toxic to leukemia L1210 in static culture than the corresponding unsubstituted analogues. While the unsubstituted aminoacridines were quite good inhibitors of Escherichia coli DNA-primed RNA polymerase, the 6-chloro-2-methoxy-substituted compounds stimulated this enzyme system. In the presence of E.coliDNA, the ESR spectrum of 4-[(6-chloro-2-methoxy-9-acridinyl)amino]-2,2,6,6-tetramethyl-1-piperidinyloxyl (12) became broad and highly asymmteric with a maximal hyperfine splitting of 57.5 G. This observation suggests that when 12 intercalates into DNA the piperidinyl moiety that bears the nitroxide group becomes highly immobilized. These results suggest that the spin-labeled 9-aminoacridines will be useful probes for nucleic acids.