Amide Analogues Research Articles

Fluorogenic Hg2+-Selective Chemodosimeter Derived from 8-Hydroxyquinoline

[reaction: see text] A new thioamide derivative of 8-hydroxyquinoline-benzothiazole was prepared, and its fluorogenic chemodosimetric behaviors toward transition-metal ions were investigated. The thioamide derivative showed highly Hg2+-selective fluorescence enhancing properties (167-fold) in 30% aqueous acetonitrile solution. The selective and sensitive signaling behaviors were found to originate from the Hg2+ ion induced transformation of the very weak fluorescent thioamide derivative into a highly fluorescent amide analogue.

Synthesis of N-alkyl substituted bioactive indolocarbazoles related to Gö6976

The syntheses of new nitrile and amide analogues of 7-keto Gö6976 are described. The amide analogue 22 was formed via the condensation with a new functionalized indoleacetic acid derivative 25 to overcome the solubility problem during the coupling reaction.

Highly antiproliferative, low-calcemic, side-chain amide and hydroxamate analogs of the hormone 1α,25-dihydroxyvitamin D 3

Four new side-chain amide ( 2 and 3) and hydroxamate ( 4 and 5) analogs of the hormone calcitriol ( 1) have been prepared. Even though lacking the 25-OH group characteristic of natural calcitriol ( 1), analogs 2– 4 are as antiproliferative in vitro as calcitriol ( 1) but are 20–40 times less calciuric in vivo than calcitriol ( 1).

Pharmacological Characterization of Novel Water-Soluble Cannabinoids

Presently, there are numerous structural classes of cannabinoid receptor agonists, all of which require solubilization for experimental purposes. One strategy for solubilizing water-insoluble tetrahydrocannabinols is conversion of the phenolic hydroxyl to a morpholinobutyryloxy substituent. The hydrochloride salts of these analogs are water-soluble and active in vivo when administered in saline. The present investigation demonstrated that hydrochloride salts of numerous substituted butyryloxy esters are water-soluble and highly potent. The substitutions include piperidine, piperazine, and alkyl-substituted amino moieties. It was also discovered that incorporation of a nitrogenous moiety in the alkyl side chain increased the pharmacological potency of tetrahydrocannabinol. For example, an analog containing a pyrazole in the side chain (O-2545) was found to have high affinity and efficacy at cannabinoid 1 (CB(1)) and CB(2) receptors, and when dissolved in saline, it was highly efficacious when administered either intravenously or intracerebroventricularly to mice. A series of carboxamido and carboxylic acid amide analogs exhibited high pharmacological potency, but their hydrochloride salts were not water-soluble. On the other hand, incorporation of imidazoles into the terminus of the side chain led to water-soluble hydrochloride salts that were highly potent when administered in saline to laboratory animals. It is now possible to conduct cannabinoid research with agonists that are water-soluble and thus obviating the need of solubilizing agents.

Teratology study of derivatives of tetramethylcyclopropyl amide analogues of valproic acid in mice

Although valproic acid (VPA) is used extensively for treating various kinds of epilepsies, it is well known that it causes neural tube and skeletal defects in both humans and animals. The amide and urea derivatives of the tetramethylcylcopropyl VPA analogue, N-methoxy-2,2,3,3-tetramethylcyclopropanecarboxamide (N-methoxy-TMCD) and 2,2,3,3-tetramethylcyclopropanecarbonylurea (TMC-urea), were synthesized and shown to have a more potent anticonvulsant activity than VPA. The objective of this study was to investigate the teratogenic effects of these compounds in NMRI mice. Pregnant NMRI mice were given a single subcutaneous injection of either VPA, N-methoxy-TMCD, or TMC-urea at 1.8 and 3.6 mmol/kg on gestation day (GD) 8. Cesarean section was performed on GD 18. First, the live fetuses were examined to detect any external malformations, then their skeletons were double-stained for bone and cartilage and subsequently examined. Significant increases in fetal losses and neural tube defects were observed with administration of VPA at 3.6 mmol/kg when compared to the vehicle control. In contrast, upon cesarean section, there were no significant differences between either N-methoxy-TMCD or TMC-urea and the control groups for any parameter. Skeletal examination revealed that a number of the abnormalities were induced by VPA dose-dependently at high rates of incidence. These abnormalities were mainly at the axial skeletal level. However, lower frequencies of skeletal abnormality were observed with N-methoxy-TMCD and TMC-urea than with VPA. In addition to their more potent antiepileptic activity, these findings clearly indicate that N-methoxy-TMCD and TMC-urea are distinctly less teratogenic than VPA in NMRI mice.

Synthesis, cannabinoid receptor activity, and enzymatic stability of reversed amide derivatives of arachidonoyl ethanolamide

Retroanandamide ( 2f) and its 10 analogues ( 1a– e, 2a– e) were synthesized and evaluated for the cannabinoid receptor activation by a [ 35S]GTPγS binding assay using rat cerebellar membranes, and Chinese hamster ovary cell membranes expressing human CB2 receptors. The primary goal of the study was to develop cannabinoid receptor agonists having improved enzymatic stability compared to endogenous N-arachidonoyl ethanolamide (AEA). Furthermore, by reversing the amide bond of AEA, the formation of arachidonic acid would be prevented. Finally, an effect of the carbonyl carbon position on the cannabinoid receptor activity was explored by synthesizing retroanandamide analogues having different chain lengths ( 1a– e, C 19; 2a– f, C 20). All the synthesized compounds, except 2c, behaved as partial agonists for the both cannabinoid receptors. In rat brain homogenate, the reversed amides possessed significantly higher stability against FAAH induced degradation than AEA. Therefore, the reversed amide analogues of AEA may serve as enzymatically stable structural basis for the drug design based on the endogenous cannabinoids.

Local Anesthetic-Induced Protection Against Lipopolysaccharide-Induced Injury in Endothelial Cells: The Role of Mitochondrial Adenosine Triphosphate-Sensitive Potassium Channels

Lidocaine attenuates cell injury induced by ischemic-reperfusion and inflammation, although the protective mechanisms are not understood. We hypothesized that lidocaine and other amide local anesthetics protect against endothelial cell injury through activation of the mitochondrial adenosine triphosphate-sensitive potassium (mitoK(ATP)) channels. We determined the effects of amide local anesthetics (lidocaine, ropivacaine, and bupivacaine), ester local anesthetics (tetracaine and procaine), one amide analog (YWI), and two non-amide local anesthetic analogs (JDA and ICM) on viability of human microvascular endothelial cells after exposure to lipopolysaccharide (LPS) in the absence or presence of the mitoK(ATP) channel antagonist 5-hydroxydecaonate. Flavoprotein fluorescence was used to investigate the effects of local anesthetics on diazoxide-induced activation of mitoK(ATP) channels. Lidocaine, ropivacaine, bupivicaine, YWI, JDA, and ICM attenuated by 60% to 70% the decrease in cell viability caused by LPS. Amide local anesthetics and YWI protection was inhibited by 5-hydroxydecaonate, whereas the protection induced by JDA and ICM was not. Tetracaine and procaine did not protect against LPS-induced injury. The amide local anesthetics and the amide analog (YWI) enhanced diazoxide-induced flavoprotein fluorescence by 5% to 20%, whereas ester local anesthetics decreased diazoxide-induced flavoprotein fluorescence by 5% to 60% and the non-amide local anesthetic analogs had no effect. In conclusion, amide local anesthetics and the amide analog (YWI) attenuate LPS-induced cell injury, in part, through activation of mitoK(ATP) channels. In contrast, tetracaine and procaine had no protective effects and inhibited activation of mitoK(ATP) channels. The non-amide local anesthetic analogs induced protection but through mechanisms independent of mitoK(ATP) channels.

Factors Dictating the Pseudocatalytic Efficiency of Avidins

The hydrolysis of biotinyl p-nitrophenyl ester (BNP) by a series of avidin derivatives was examined. Surprisingly, a hyperthermostable avidin-related protein (AVR4) was shown to display extraordinary yet puzzling hydrolytic activity. In order to evaluate the molecular determinants that contribute to the reaction, the crystal structure of AVR4 was compared with those of avidin, streptavidin and key mutants of the two proteins in complex with biotinyl p-nitroanilide (BNA), the inert amide analogue of BNP. The structures revealed that a critical lysine residue contributes to the hydrolysis of BNP by avidin but has only a minor contribution to the AVR4-mediated reaction. Indeed, the respective rates of hydrolysis among the different avidins reflect several molecular parameters, including binding-site architecture, the availability of the ligand to solvent and the conformation of the ligand and consequent susceptibility to efficient nucleophilic attack. In avidin, the interaction of BNP with Lys111 and disorder of the L3,4 loop (and consequent solvent availability) together comprise the major driving force behind the hydrolysis, whereas in AVR4 the status of the ligand (the pseudo-substrate) is a major distinguishing feature. In the latter protein, a unique conformation of the L3,4 loop restrains the pseudo-substrate, thereby exposing the carbonyl carbon atom to nucleophilic attack. In addition, due to its conformation, the pseudo-substrate in the AVR4 complex cannot interact with the conserved lysine analogue (Lys109); instead, this function is superseded by polar interactions with Arg112. The results demonstrate that, in highly similar proteins, different residues can perform the same function and that subtle differences in the active-site architecture of such proteins can result in alternative modes of reaction.

Synthesis and transdermal permeation-enhancing activity of ketone, amide, and alkane analogs of Transkarbam 12

Transkarbam 12 (5-(dodecyloxycarbonyl)pentylammonium-5-(dodecyloxycarbonyl)pentylcarbamate, T12) is a highly active transdermal permeation enhancer. In this study, ketone, amide, and alkane analogs of T12 have been synthesized and evaluated for their permeation-enhancing activity using porcine skin and theophylline as a model drug. Replacement of ester by methylene and ketone, respectively, led to a significant decrease of activity. Amide analogs displayed lower activity in 60% propylene glycol and were comparable to T12 in isopropyl myristate. An intramolecular H-bond between ester and ammonium-carbamate group was suggested to be important for the permeation-enhancing activity of T12.

Synthesis and antitumor activity of simplified ecteinascidin–saframycin analogs

Two series of simplified analogs of the ecteinascidin–saframycin type alkaloids were prepared from l-DOPA. Their in vitro antitumor activity was tested against three human cancer cell lines (HCT-8 colon carcinoma, Bel-7402 liver carcinoma, and BGC-823 gastric carcinoma). Among these compounds, the ester analogs have stronger activities than those of amide analogs in general. Among them, 1-naphthalene carboxylate ester analog 31 has the strongest activity against BGC-823 cells.

Synthesis and Evaluation of 1-Deoxy-d-xylulose 5-Phosphate Analogues as Chelation-Based Inhibitors of Methylerythritol Phosphate Synthase

[structures: see text] A series of 1-deoxy-D-xylulose 5-phosphate (DXP) analogues were synthesized and evaluated as inhibitors of E. coli methylerythritol phosphate (MEP) synthase. In analogues 1-4, the methyl group in DXP was replaced by hydroxyl, hydroxylamino, methoxy, and amino moieties, respectively. In analogues 5 and 6, the acetyl moiety in DXP was replaced by hydroxymethyl and aminomethyl groups. These compounds were designed to coordinate to the active site divalent metal in MEP synthase. The carboxylate (1), methyl ester (3), amide (4), and alcohol (5) analogues were inhibitors with IC50's ranging from 0.25 to 1.0 mM. The hydroxamic acid (2) and amino (6) analogues did not inhibit the enzyme.

New metabolically stable fatty acid amide ligands of cannabinoid receptors: Synthesis and receptor affinity studies

We investigated the structure–activity relationships for the interactions of fatty acid amide analogs of the endocannabinoid anandamide with human recombinant cannabinoid receptors. Thirty-five novel fatty acid amides were synthesized using five different types of acyl chains and 11 different aromatic amine ‘heads.’ Although none of the new compounds was a more potent ligand than anandamide, we identified three amine groups capable of improving the metabolic stability of arachidonoylamides and their CB 1/CB 2 selectivity ratio to over 20-fold, and several aromatic amines capable of improving the affinity of short chain or monosaturated fatty acids for cannabinoid CB 1 receptors. For the first time a tertiary amide of arachidonic acid was found to possess moderate affinity ( K i = 300 nM) for cannabinoid CB 1, but not CB 2, receptors.

5-Amino-2-carbonylthiophene derivatives for use as p38 MAPK inhibitors in the treatment of inflammatory diseases

This recent patent application from Astex (WO2004089929) describes p38 inhibitors containing uncyclised amides or ureas. Other urea and amide inhibitors of p38 are in the prior art. The present invention is based on the substitution pattern on a thiophene scaffold to which the amides and ureas are attached. An earlier patent application from Astex (WO2004004720) describes p38 inhibitors in which the generic structures do not require amides or ureas. However, the earlier patent application provides some structure–activity relationships (SARs) in which the most potent analogues are amides or ureas. Common structural features are apparent for the likely potent acyclic amide and ureas in the two Astex patent applications. These features may also connect the functionality in the Astex compounds to similar structures in competitor acyclic amide and urea p38 inhibitors. Crystallography data on two series of competitor acyclic urea and amide analogues have been reported.

Screening a natural product-based combinatorial library using FTICR mass spectrometry

This manuscript reports the use of Fourier transform ion cyclotron resonance mass spectrometry to screen a combinatorially generated natural product-based library for binding affinity to bovine carbonic anhydrase II (bCAII). The fungal natural product 3-chloro-4-hydroxyphenylacetamide was the library template, with 11 secondary amide analogues of this template constituting the combinatorial library. 2-(3-Chloro-4-hydroxyphenyl)- N-(4-sulfamoylphenethyl)acetamide (compound 11) of this library was identified as a tight binding inhibitor of bCAII, by detection of a noncovalent complex corresponding to [bCAII + 11] in the mass spectrum. A competitive bCAII enzyme binding assay validated the mass spectrometry screening result. The equilibrium dissociation constant ( K i) for 11 was measured as 77.4 nM. Preliminary structure–activity investigations of the bioactive natural product analogue are also reported.

Efficacy of antiepileptic tetramethylcyclopropyl analogues of valproic acid amides in a rat model of neuropathic pain

Antiepileptic drugs (AEDs) are widely utilized in the management of neuropathic pain. The AED valproic acid (VPA) holds out particular promise as it engages a variety of different anticonvulsant mechanisms simultaneously. However, the clinical use of VPA is limited by two rare but potentially life-threatening side effects: teratogenicity and hepatotoxicity. We have synthesized several tetramethylcyclopropyl analogues of VPA amides that are non-teratogenic, and are likely to be non-hepatotoxic, and that exhibit good antiepileptic efficacy. In the present study we have assessed the antiallodynic activity of these compounds in comparison to VPA and gabapentin (GBP) using the rat spinal nerve ligation (SNL) model of neuropathic pain. TMCA (2,2,3,3-tetramethylcyclopropanecarboxylic acid, 100–250 mg/kg), TMCD (2,2,3,3-tetramethylcyclopropanecarboxamide, 40–150 mg/kg), MTMCD ( N-methyl-TMCD, 20–100 mg/kg), and TMCU (2,2,3,3-tetramethylcyclopropanecarbonylurea, 40–240 mg/kg) all showed dose-related reversal of tactile allodynia, with ED 50 values of 181, 85, 41, and 171 mg/kg i.p., respectively. All were more potent than VPA (ED 50 = 269 mg/kg). An antiallodynic effect was obtained for TMCD, MTMCD and TMCU at plasma concentrations as low as 23, 6 and 22 mg/L, respectively. MTMCD was found to be non-toxic, non-sedative and equipotent to gabapentin, currently the leading AED in neuropathic pain treatment. Tetramethylcyclopropyl analogues of VPA amides have potential to become a new series of drugs for neuropathic pain treatment.

Misidentification of prostamides as prostaglandins

Prostaglandins and endogenous cannabinoid metabolites share the same lipid backbone with differing polar head groups at exactly the position through which a large molecule is attached to provide antigenicity and thus raise antisera. Hence, we hypothesized that antisera raised against prostaglandins linked to a large molecule such as BSA at the carboxyl functional group would also recognize endogenous cannabinoid metabolites and lead to highly misleading interpretations of data. We found major cross-reactivity of commercial antisera raised to prostaglandins with endocannabinoid metabolites. Furthermore, in a well-characterized cell line (WISH) or primary amnion tissue explants, endocannabinoid treatment led to increased production of endocannabinoid metabolites as opposed to primary prostaglandins. This was apparent only after separation of products by thin-layer chromatography, because they measured as prostaglandins by radioimmunoassay. These findings have major implications for our interpretation of data in situations in which these prostaglandin-like molecules are formed, and they stress the need for chromatographic or spectrometric confirmation of prostaglandin production detected by antibody-based methods.

Synthesis of long-chain amide analogs of the cannabinoid CB1 receptor antagonist N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3-carboxamide (SR141716) with unique binding selectivities and pharmacological activities

An extended series of alkyl carboxamide analogs of N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl- 1 H-pyrazole-3-carboxamide (SR141716; 5) was synthesized. Each compound was tested for its ability to displace the prototypical cannabinoid ligands ([ 3H]CP-55,940, [ 3H] 2; [ 3H]SR141716, [ 3H] 5; and [ 3H]WIN55212-2, [ 3H] 3), and selected compounds were further characterized by determining their ability to affect guanosine 5′-triphosphate (GTP)-γ-[ 35S] binding and their effects in the mouse vas deferens assay. This systematic evaluation has resulted in the discovery of novel compounds with unique binding properties at the central cannabinoid receptor (CB1) and distinctive pharmacological activities in CB1 receptor tissue preparations. Specifically, compounds with nanomolar affinity which are able to fully displace [ 3H] 5 and [ 3H] 2, but unable to displace [ 3H] 3 at similar concentrations, have been synthesized. This selectivity in ligand displacement is unprecedented, in that previously, compounds in every structural class of cannabinoid ligands had always been shown to displace each of these radioligands in a competitive fashion. Furthermore, the selectivity of these compounds appears to impart unique pharmacological properties when tested in a mouse vas deferens assay for CB1 receptor antagonism.

Exploration of a binding mode of indole amide analogues as potent histone deacetylase inhibitors and 3D-QSAR analyses

Docking simulations and three-dimensional quantitative structure–activity relationship (3D-QSAR) analyses were conducted on a series of indole amide analogues as potent histone deacetylase inhibitors. The studies include comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Selected ligands were docked into the active site of human HDAC1. Based on the docking results, a novel binding mode of indole amide analogues in the human HDAC1 catalytic core is presented, and enzyme/inhibitor interactions are discussed. The indole amide group is located in the open pocket, and anchored to the protein through a pair of hydrogen bonds with Asp99 O-atom and amide NH group on ligand. Based on the binding mode, predictive 3D-QSAR models were established, which had conventional r 2 and cross-validated coefficient values ( r cv 2 ) up to 0.982 and 0.601 for CoMFA and 0.954 and 0.598 for CoMSIA, respectively. A comparison of the 3D-QSAR field contributions with the structural features of the binding site showed good correlation between the two analyses. The results of 3D-QSAR and docking studies validate each other and provided insight into the structural requirements for activity of this class of molecules as HDAC inhibitors. The CoMFA and CoMSIA PLS contour maps and MOLCAD-generated active site electrostatic, lipophilicity, and hydrogen-bonding potential surface maps, as well as the docking studies, provided good insights into inhibitor–HDAC interactions at the molecular level. Based on these results, novel molecules with improved activity can be designed.

Vinylogous amide analogs of methylphenidate

In an effort to produce compounds with longer durations of action, we attempted to synthesize ketone analogs of methylphenidate which, however, appear to be highly unstable due to a highly acidic proton alpha to the ketone and phenyl groups. Nevertheless, vinylogous amide by products have been synthesized and tested for activity at dopamine, norepinephrine, and serotonin transporters. The compounds were found to be weak inhibitors of monoamine reuptake despite rigid three dimensional structures that are quite similar to the global minimum of threo-( R, R)-methylphenidate. The structures were confirmed by X-ray crystallography.

Synthesis and antibacterial activity of hydrolytically stable (−)-epicatechin gallate analogues for the modulation of β-lactam resistance in Staphylococcus aureus

Hydrolytically more stable analogues of (−)-epicatechin gallate (ECg) have been synthesised from ECg where an amine or amide function has been substituted for the ester linkage that joins the C-ring with the galloyl D-ring. Sub-inhibitory concentrations (25mg/L) of the amide analogue 7, possessing the natural C-3 stereochemistry, were able to reduce the resistance to oxacillin of three strains of methicillin resistant Staphylococcus aureus (BB 568, EMRSA-15 and EMRSA-16) comparable to levels achieved with ECg.