Carvedilol - DrugBank
Structure–Activity Relationship Studies of Indole-Based Compounds as Small Molecule HIV-1 Fusion Inhibitors Targeting Glycoprotein β adrenergic receptor antagonists were initially developed in the s, for the treatment of . A beta-blocker. Metoprolol . Figure 8 shows the structure-activity relationship (SAR) for β-blockers. For the function The aromatic ring can either be benzoheterocyclic (such as indole) or heterocyclic (such as thiadiazole). This is. Structure activity relationship (SAR)of sympathomimetic amines, Adrenergic antagonist and Neurone blockers Beta and alpha 1 blocker: Labetolol, Carvedilol.
When following both pathways, the central chiral carbon preserves its configuration, which is an important part to consider when synthesizing enantiomerically defined drugs. The ring opening of the epoxide ring in glycidic ether is done with an appropriate amine, such as isopropyl amine or tert-butylamine, and leads to the aryloxypropanolamine compound that consist of a secondary amine.
The alcohol is oxidized by using 2-Iodoxybenzoic acid IBX to give aldehyde. Finally the diol is converted to epoxide using the Mitsunobu reaction and stirred with isopropyl amine in CH2Cl2 to give S -propranolol.
The oxymethylene bridge of propranolol can be seen inside the green ring.
Discovery and development of beta-blockers
The length of the side chain is increased when an oxymethylene bridge is introduced. It has been shown that the side chains of aryloxypropanolamine can adopt a conformation that puts the hydroxyl and amine groups in more or less the same position as with beta blocker that do not have this group as a part of the side chain.
It was suspected that propranolol's centrally induced side effects could be due to its high lipophilicity. Thus, it was focused on synthesizing analogues with hydrophilic moieties, favourably placed to see if the side effects would decrease.
Selecting para-acylamino groups as the hydrophilic moiety, scientists synthesized a group of para-acylphenoxyethanol and propanolamines, and selected practolol for clinical trials. The aromatic ring can either be benzoheterocyclic such as indole or heterocyclic such as thiadiazole.
Large para-substituents usually decrease activity but large ortho-groups retain some activity. Polysubstitution on carbon 2 and 6 makes the compound inactive but when the substitution is on carbon 3 and 5 there's some activity.
For the highest cardioselectivity, the substituents should be as following: They have proved to reduce morbidity and mortality. The reason is probably because of their anti-arrhythmic effects and also anti-ischemic effects. The therapy has been very helpful for high-risk patients.
These diseases are mentioned in the following sub-chapters. A novel preparation of the electrogenerated cyanomethyl anion as an electrogenerated base, in the synthesis of substituted indoles from alkynylanilines was developed. The workup process only requires filtration or flash chromatography of the evaporated reaction mixture. It was reported that this electrochemical approach represents an important alternative to the previous procedures.
Synthesis of 2-phenyl indole derivative by cyclization of 1a induced by the electrogenerated cyanomethyl anion under different reaction conditions [ 32 ]. The effect of indole and 5-chloroindole on the anodic dissolution of copper in acidic sodium chloride solutions was studied using voltammetry on a rotating disc electrode RDE [ 33 ]. The influence of these organic additives on the electrodeposition of copper on platinum was also investigated using RDE and electrochemical quartz crystal microbalance EQCM techniques.
The EQCM measurements show that a sparingly soluble layer of the inhibitor is responsible for the protective effects observed in chloride solutions. A new voltammetric method was successfully used to detect indoleacetic acid IAA; Scheme 5 in some plant leaves. Sodium dodecyl sulfate SDSan anionic surfactant, can strongly adsorb at the surface of a carbon paste electrode CPE via the hydrophobic interaction.
The experimental parameters, such as pH, varieties of surfactants, concentration of SDS, and scan rate were optimized for IAA determination [ 34 ]. Chemical formula of indoleacetic acid.
Metabolization usually progressed through the addition or the modification of a substituent; this will give rise to additional waves or to a shift of the main wave due to the metabolites.
Electrochemical Behavior of Biologically Important Indole Derivatives
CV has been used in studying the redox mechanism that is related to antioxidant activity of synthesized indolepropionamide Scheme 6 [ 21 ]. Based on this study, a simple, rapid, and sensitive voltammetric method was developed for the determination of the indole derivatives that are readily oxidized at the carbon-based electrodes. The oxidative behavior of the indole derivatives was studied as a function of pH at a glassy carbon electrode.
The results showed that the compounds might have profound effects on our understanding of their in vivo redox processes and pharmaceutical activity. It was assumed that the oxidation step of indolic compounds is located on the nitrogen atom in the indole ring of the molecule, which is electroactive in both acidic and basic media, leading finally to hydroxylation of benzene ring. Chemical formula of indolepropionamides [ 21 ].
Electrochemical techniques offer important information about drug molecules and their mechanisms in the body, such as metabolism, which is one of the important actions in drug discovery. Two compounds, namely, 1-methylindolecarboxaldehyde isonicotinoyl hydrazone Scheme 7 a and 5-chloro-1H-indolecarboxaldehyde isonicotinoyl hydrazone Scheme 7 b were synthesized, characterized, and examined electrochemically using different voltammetric techniques in order to evaluate the possible biological behavior [ 35 ].
A linear response was obtained in the different media for the compounds with low detection limits of the synthesized compounds. Chemical formula of 1-methylindolecarboxaldehyde isonicotinoyl hydrazone a and 5-chloro-1H-indolecarboxaldehyde isonicotinoyl hydrazone b. Electrochemical behavior of some indolyl-thiohydantoin derivatives Scheme 8 was studied in order to understand the electrochemical process that occurs on the glassy carbon electrode, both pH and scan rate [ 36 ].
For the quantitative determination, differential pulse voltammetric methods were applied.
It was assumed that the oxidation steps occur for all the compounds on the nitrogen atom in the indole ring, which is electroactive in both acidic and basic media, leading finally to hydroxylation of the benzene ring.
Studies of electrochemical oxidation of indole and some derivatives showed that the indole ring is most likely form dimers and trimers. This technique has been successfully applied to trace measurements of important pharmaceutical compounds.
Chemical formula of indolyl-thiohydantoin derivatives. The use of electrochemistry and combination of this method with other analytical techniques are becoming one of the important approaches in drug discovery. Many physiological processes depend on oxidoreduction reactions in the body. For that reason, it may be possible to find similarities between electrochemical and biochemical reactions. In a review by Suzen and Ozkan [ 37 ], the latest developments related to the use of electrochemical techniques in drug research will be surveyed in order to evaluate possible combinations of spectrometric methods with electrochemical techniques, were presented.
The use of electrochemistry and combination with spectroscopic techniques are becoming one of the important approaches in drug discovery and research. In a review published by Greci et al. It is known that radical cations can be generated from substrates with low oxidation potentials by electrochemical oxidation.
For some researchers, many reactions interpreted by an electron transfer process actually occur through an ionic mechanism while others, described by an ionic mechanism, involve an electron transfer process [ 38 ].
Radical cations of primary aromatic amines were unable to attack nucleophiles such as 2-phenyl-1H-indole. The interaction between 2-phenyl-1H-indole, and primary aromatic amines may only occur through coupling of their neutral radicals. The 2-phenyl-1H-indolyl radical cation can dimerise as observed for tetrahydrocarbazoles, but dimerisation is faster when it reacts via the indolyl radical. As a result, 2-phenyl-1H-indole reacts with p-anisidine, 2-nitro-p-anisidine, and 2-nitro-p-methylaniline, under anodic oxidation, to give several products, depending on the potential used and on the presence or the absence of oxygen and a deprotonating agent.
This study gives new information about the reactivity of radical cations generated by a controlled anodic potential and neutral radicals. Some 2-phenyl indole 2PI; Scheme 9 derivatives were investigated electroanalytically by voltammetric determination as a function of pH at a glassy carbon and hanging mercury drop electrodes in different buffer media [ 29 ].
The studied molecules are extensively metabolized in vivo, mainly through oxidative processes in which we assume that the oxidation step of indolic compounds is located on the nitrogen atom in the indole ring of the molecule.
Based on this study, simple, rapid, sensitive and validated voltammetric method was developed for the determination and investigation of electrochemical behaviour of the 2PI derivatives. Chemical formula of 2-phenyl indole derivatives. They used a voltammetric study and the oxidation potentials to make a correlation to the scavenging activity reported for the studied indoles.
The study included several tryptophan and tryptamine derivatives. All the compounds showed an oxidation potential peak lower than that observed for indole, but higher than that described for the antioxidant melatonin. The electrochemical behavior showed a high correlation with the scavenging activity of peroxyl radical, for selected compounds.
It was observed that for some reactive species the scavenging mechanism involves electron transfer while for other species some structural requirements, such as the steric hindrance between the substrate and the bulky oxidant, should be considered when analyzing the scavenging activity. A method has been developed for the simultaneous determination of MLT and pyridoxine hydrochloride in pharmaceutical dosage forms by DPV, based on the oxidation of both drugs at a glassy carbon electrode [ 40 ].
Cyclic and linear scan voltammetry were used to examine the influence of pH, nature of the buffer, scan rate, and concentration.
The proposed method was successfully applied to the commercial tablets containing this drug combination without any interference by the excipients. Indole and its metabolites e. The electrochemical behavior of tryptophan and its derivatives, such as indoleacetic acid, 5-hydroxytryptamine Scheme 10 a5-hydroxy-indoleacetic acid, and glycyl-tryptophan Scheme 10 b peptide at a glassy carbon electrode modified with hemin natural metalloporphyrin by electropolymerization have been investigated in detail [ 44 ].
The results indicated that a two-electron and two-proton transfer was involved in the electrode reaction process. Chemical formula of 5-Hydroxytryptamine a and Glycyl-tryptophan b. Tryptophan is an essential amino acid for humans and a precursor for serotonin, melatonin, and niacin.
It has been implicated as a possible cause of schizophrenia in people who cannot metabolize it properly. Therefore, simple, sensitive, and less expensive detection of tryptophan is of great interest. Concentration of amino acids in biological samples is low; therefore, it is necessary to use a highly sensitive method that provides determination of these analytes at subordinate concentrations.
Electroanalytical technique is an attractive method due to simplicity, low expense, high sensitivity, and possibility of miniaturization. In a study [ 45 ], a modified carbon paste electrode was prepared by using TiO2 nanoparticles and ferrocene carboxylic acid FCCa in carbon paste matrix.
High sensitivity and selectivity together with very low detection limit of the electrode response make it very suitable for simultaneous and individual determination of trace amounts of GSH and tryptophan in pharmaceutical and clinical preparations. A complete resolution between DPV peak of tryptophan from those of cysteine and ascorbic acid provides a very suitable and effective method for simultaneous determination of tryptophan, cysteine, and ascorbic acid in pharmaceutical and clinical preparations.
Studies on the Indole Ring Containing Drugs The electrochemical oxidation of sertindole Scheme 11 athe newer atypical antipsychotic was investigated using cyclic, linear sweep voltammetry at a glassy carbon and boron-doped diamond electrodes [ 47 ]. Sertindole levels were determined in serum and pharmaceutical formulations, by means of electrochemical methods. In CV, depending on pH values, sertindole showed one or two irreversible oxidation responses that were found related to the different electroactive part of the molecule.
Using second and sharp oxidation peak, two voltammetric methods were described for the determination of sertindole by differential pulse and squarewave voltammetry at the glassy carbon and boron-doped diamond electrodes. To find out the relationship between the oxidative behavior and protonation constant, value of sertindole was determined.
The proposed methods might be alternatives to the LC techniques in therapeutic drug monitoring or the experimental data might be used for the development LC-EC method. Sertindole aziprasidone band carvedilol c. Another psychotropic agent, Ziprasidone Scheme 11 bused for the treatment of schizophrenia was investigated electrochemically at boron-doped diamond and glassy carbon electrodes using cyclic, differential pulse, and squarewave voltammetry [ 48 ].
The dependence of the peak current and peak potentials on pH, concentration, nature of the buffer, and scan rate were examined.
The proposed methods were applied for the determination of ziprasidone from pharmaceutical dosage forms and human serum samples without any time-consuming extraction, separation, evaporation, or adsorption steps prior to drug assay except precipitation of the proteins using acetonitrile.
The results were statistically compared with those obtained through an established LC-UV technique, no significant differences were been found between the voltammetric and LC methods. It is used in the management of hypertension and angina pectoris and as an adjunct to standard therapy in symptomatic heart failure [ 49 ].
The electrochemical oxidation of carvedilol was investigated using cyclic, linear sweep voltammetry at a glassy carbon electrode [ 50 ]. These methods were successfully applied for the analysis of carvedilol pharmaceutical dosage forms and spiked human serum samples and were found to be rapid, requiring less than 7 min to run a sample.
The electrochemical oxidation of carvedilol molecule has two irreversible electrode processes and both of them are pH dependent. No electroactive interferences from the tablet excipients and endogenous substances from biological material were found. These recovery results reveal that the proposed methods had adequate precision and accuracy, and, consequently, can be applied to the determination of carvedilol without any interference from tablet excipients.
Naratriptan exhibits an anodic response in aqueous media over a broad pH range pH 2—12as determined by DPV and CV using glassy carbon electrodes. This response is irreversible in nature, diffusion controlled, and, probably, caused by the oxidation of the naratriptan indole moiety.
Selectivity trials revealed that the oxidation signal of the drug was not disturbed by the presence of excipients or degradation products. It was concluded that the method offered is useful for the quantification of naratriptan in pharmaceutical drugs and that this method requires no separations or extractions.
The method was found not to be time consuming and is inexpensive when compared with the Pharmacopoeial HPLC method. Chemical formula of naratriptan aindomethacin band acemethacin c. Indomethacin, 1- p-chlorbenzoil 5-metoxymethylindolylacetic acid Scheme 12 b is an important nonsteroidal anti-inflammatory drug, derived from indol, used in the treatment of some forms of inflammatory and degenerative diseases of articulations [ 5253 ].
A boron-doped diamond electrode was used to examine the possibility of anodic detection and determination of indomethacin by CV. The oxidation of this drug exhibited an irreversible character.
Very sensitive output signal to low concentrations has been associated with a relative high background current. Scan rate dependencies suggested a diffusion-controlled process complicated by certain surface effects [ 53 ]. In another study, procedures for the determination of indomethacin and acemetacin Scheme 12 c by differential pulse adsorptive stripping voltammetry with a mercury electrode have been described and optimized [ 54 ].
In a different study, the reduction of acemetacin was established using linear-sweep voltammetry at Hg electrode [ 55 ]. Indomethacin and acemetacin in urine were determined with good results and without the need for prior separation. Determination of indomethacin was described by a fully validated squarewave adsorptive cathodic stripping voltammetric procedure [ 56 ]. The proposed procedure was successfully applied for determination of the drug in tablets and human serum with good recoveries.
Fluvastatin sodium Fluvastatin; Scheme 13 a is a water-soluble cholesterol-reducing agent which acts by inhibition of 3-hydroxymethylglutaryl-coenzyme A reductase.
The oxidation of fluvastatin sodium on a glassy carbon electrode has been studied by use of a variety of voltammetric techniques [ 43 ]. Oxidation of fluvastatin sodium was found to be diffusion controlled and irreversible.
The best results for the determination of fluvastatin sodium were obtained by using differential pulse and squarewave voltammetric techniques. The proposed methods were successfully applied to the determination of the drug in capsules and biological fluids. Determination of fluvastatin sodium in Loscol capsule and the electrochemical behavior of fluvastatin sodium on a glassy carbon electrode were investigated by CV, linear sweep voltammetry, and DPV by Yan [ 57 ].
Fluvastatin sodium gave a sensitive oxidation peak under the differential pulse voltammetric mode. The electrochemical analysis method described in the study enables simple and rapid determination of fluvastatin sodium in real samples.