Indole Analogues Research Articles

Comparison of the Binding and Functional Properties of Two Structurally Different D2 Dopamine Receptor Subtype Selective Compounds

We previously reported on the synthesis of substituted phenyl-4-hydroxy-1-piperidyl indole analogues with nanomolar affinity at D2 dopamine receptors, ranging from 10- to 100-fold selective for D2 compared to the D3 dopamine receptor subtype. More recently, we evaluated a panel of aripiprazole analogues, identifying several analogues that also exhibit D2 vs D3 dopamine receptor binding selectivity. These studies further characterize the intrinsic efficacy of the compound with the greatest binding selectivity from each chemical class, 1-((5-methoxy-1H-indol-3-yl)methyl)-4-(4-(methylthio)phenyl)piperidin-4-ol (SV 293) and 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (SV-III-130s), using an adenylyl cyclase inhibition assay, a G-protein-coupled inward-rectifying potassium (GIRK) channel activation assay, and a cell based phospho-MAPK (pERK1/2) assay. SV 293 was found to be a neutral antagonist at D2 dopamine receptors using all three assays. SV-III-130s is a partial agonist using an adenylyl cyclase inhibition assay but an antagonist in the GIRK and phospho ERK1/2 assays. To define the molecular basis for the binding selectivity, the affinity of these two compounds was evaluated using (a) wild type human D2 and D3 receptors and (b) a panel of chimeric D2/D3 dopamine receptors. Computer-assisted modeling techniques were used to dock these compounds to the human D2 and D3 dopamine receptor subtypes. It is hoped that these studies on D2 receptor selective ligands will be useful in the future design of (a) receptor selective ligands used to define the function of D2-like receptor subtypes, (b) novel pharmacotherapeutic agents, and/or (c) in vitro and in vivo imaging agents.

Indole Molecules As Inhibitors Of Tubulin Polymerization: Potential New Anticancer Agents

Agents that interfere with tubulin function have a broad anti-tumor spectrum and they represent one of the most significant classes of anticancer agents. In the past few years, several small synthetic molecules that have an indole nucleus as a core structure have been identified as tubulin inhibitors. Among these, several aroylindoles, arylthioindoles, diarylindoles and indolylglyoxyamides have shown good inhibition towards the tubulin polymerization. This article reviews the synthesis, biological activities and SARs of these main classes of indoles. Brief mention has also been made about the fused indole analogs as tubulin inhibitors.

The Synthesis and Antimicrobial Activity of Heterocyclic Derivatives of Totarol.

The synthesis and antimicrobial activity heterocyclic analogs of the diterpenoid totarol are described. An advanced synthetic intermediate with a ketone on the A-ring is used to attach fused heterocycles and a carbon-to-nitrogen atom replacement is made on the B-ring by de novo synthesis. A-ring analogs with an indole attached exhibit, for the first time, enhanced antimicrobial activity relative to the parent natural product. Preliminary experiments demonstrate that the indole analogs do not target the bacterial cell division protein FtsZ as had been hypothesized for totarol.

Synthesis, antimicrobial and antioxidant activities of some new indole derivatives containing pyridopyrimidine and pyrazolopyridine moieties

New indole analogues containing pyrido[2,3-d]pyrimidin-4-(3H)-ones (3a–i), pyrazolo[3,4-b]pyridin-3-amines (4a–i) and pyrido[2,3-d]pyrimidin-4-amines (5a–i) were synthesized using appropriate synthetic routes. These newly synthesized compounds were screened for their antimicrobial and antioxidant activities. Compounds 3a, 3g, 4c, 4h, 4i, 5a, 5c and 5f exhibited good antibacterial and antifungal activities. The compounds 3b, 3c, 3g, 4a, 4h, 4i and 5a exhibited good radical scavenging activity. Compounds 3a and 4d exhibited good metal chelating activity compare with standards.

Novel Inhibitors of Neurotropic Alphavirus Replication That Improve Host Survival in a Mouse Model of Acute Viral Encephalitis

Arboviral encephalitis is a potentially devastating human disease with no approved therapies that target virus replication. We previously discovered a novel class of thieno[3,2-b]pyrrole-based inhibitors active against neurotropic alphaviruses such as western equine encephalitis virus (WEEV) in cultured cells. In this report, we describe initial development of these novel antiviral compounds, including bioisosteric replacement of the 4H-thieno[3,2-b]pyrrole core with indole to improve metabolic stability and the introduction of chirality to assess target enantioselectivity. Selected modifications enhanced antiviral activity while maintaining low cytotoxicity, increased stability to microsomal metabolism, and also revealed striking enantiospecific activity in cultured cells. Furthermore, we demonstrate improved outcomes (both symptoms and survival) following treatment with indole analogue 9h (CCG-203926) in an in vivo mouse model of alphaviral encephalitis that closely correlate with the enantiospecific in vitro antiviral activity. These results represent a substantial advancement in the early preclinical development of a promising class of novel antiviral drugs against virulent neurotropic alphaviruses.

Prospective acetylcholinesterase inhibitory activity of indole and its analogs

Acetylcholinesterase (AChE) inhibitory activity is one of the proposed targets for indole analogs. Simple indoles with substitution of methoxy, carboxy or hydroxy at the benzene ring showed a low percent of inhibitory activity in eel-AChE. Adding a side chain at the pyrrole ring, such as serotonin, β-carbolines and quinolines (the bioisostere of indole), improved the inhibitory activity significantly. However, proper substitution and conformation of the ring were required for good binding. The result of inhibition in human-AChE of serotonin, β-carbolines and quinolines showed similar profile as eel-AChE with lower magnitude. The data from molecular docking showed that they shared the same binding site as galantamine.

Synthesis and Evaluation of the Cytotoxicities of Tetraindoles: Observation that the 5-Hydroxy Tetraindole (SK228) Induces G2Arrest and Apoptosis in Human Breast Cancer Cells

Current chemical and biological interest in indole-3-carbinol (I3C) and its metabolites has resulted in the discovery of new biologically active indoles. As part of a program aimed at the development of indole analogues, tetraindoles 1-15 were prepared and their antiproliferative effects on human breast cancer cells were evaluated. The results show that the 5-hydroxy-tetraindole 8 (SK228) has optimum antiproliferative activity against breast adenocarcinoma (MCF 7 and MDA-MB-231) cells and that this activity involves G(2)-phase arrest of the cell cycle with a distinctive increase in the expression of cyclin B1 and phospho-cdc2. Further observations suggest that 5-hydroxy-tetraindole 8 induces apoptosis through externalization of membrane phosphatidylserine, DNA fragmentation, and activation of caspase-3. Given the fact that I3C and its metabolites have been shown to improve therapeutic efficacy and to have a broad range of antitumor activities in human cancer cells, the current findings have important pharmacological relevance as they open a promising route to the development of a potential chemotherapeutic application of tetraindoles as agents for the treatment of breast cancer.

Epiminocyclohepta[b]indole analogs as 5-HT6 antagonists

A new series of epiminocyclohepta[b]indoles with potent 5-HT6 antagonist activity were discovered and optimized using in vitro protocols. One compound from this series was progressed to advanced pharmacokinetic (PK) studies followed by 5-HT6 receptor occupancy studies. The compound was found to have excellent oral absorption, a highly favorable PK profile and demonstrated pharmacodynamic interaction with the 5-HT6 receptor as shown by ex vivo autoradiography.

Studies on the euglycemic and hypolipidemic potentials of the novel indole analogue of thiazolidinedione, DRF 2189.

Euglycemic and hypolipidemic activities of a novel indole analogue of thiazolidinedione, DRF 2189 (CAS 172647-53-9), have been evaluated in different animal models. Compared to troglitazone (CAS 97322-87-7), DRF 2189 exhibited interesting plasma glucose and triglyceride lowering activity in genetically diabetic and obese db/db mice. It also produced a significant reduction in plasma glucose, triglyceride, total cholesterol levels and improvement in oral glucose tolerance in another genetic mouse model, the ob/ob mice. In high-fat diet fed Sprague-Dawley rats, DRF 2189 treatment showed improvement in plasma lipid parameters. Like other thiazolidinediones, this compound also possesses peroxisome proliferator activated receptor gamma (PPAR gamma) transactivation potential. In anaesthetized rat experiment, DRF 2189 produced a transient fall in blood pressure without any change in the ECG pattern. It showed non-specific smooth muscle relaxant activity against acetylcholine, histamine and potassium chloride induced contractions in isolated guinea pig ileum. A twenty-eight-day toxicity study in Wistar rats did not show any signs of treatment related adverse effects. The overall antidiabetic and hypolipidemic activities of DRF 2189 are comparable with rosiglitazone (CAS 155141-29-0) and superior to troglitazone. In conclusion, results from these preclinical studies indicate that DRF 2189, a novel thiazolidinedione, has a marked potential for the management of type-2 diabetes.

Synthesis, antimicrobial, and antioxidant activities of some new indole analogues containing pyrimidine and fused pyrimidine systems

To examine new leads with potential antimicrobial and antioxidant activities, a new series of tetrahydropyrimidines (2a–c, 3a–c and 4a–c), pyrazolo[3,4-d]pyrimidines (5a–c), and ditetrazolo[1,5-a;1′,5′-c]pyrimidines (6a–c) were synthesized in this study using appropriate synthetic routes. The newly synthesized compounds have been tested for their antimicrobial and antioxidant activities against DPPH stable free radical. In the case of antibacterial activity, compounds 2a, 6a, and 6c exhibited the maximum zone of inhibition against Staphylococcus aureus; compound 6c exhibited maximum zone of inhibition against Pseudomonas aeruginosa; and compound 2a showed maximum inhibitory growth against Klebsiella pneumonia. While in the case of antifungal activities, compound 5a showed good zone of inhibition against Aspergillus oryzae, compounds 2b and 6a exhibited maximum zone of inhibition against Aspergillus niger. In case of antioxidant activities, compound 2a showed the highest DPPH radical scavenging activity.

Synthesis of some analogues of (±)gelliusine F, (±)gelliusine E, and total synthesis of 2,2-di(6′-bromo-3′-indolyl)ethylamine

Synthesis of some analogues of indole based marine alkaloid (±)gelliusine F, (±)gelliusine E, and total synthesis of 2,2-di(6′-bromo-3′-indolyl)ethylamine are reported.

Solvent-free, microwave assisted Knoevenagel condensation of novel 2,5-disubstituted indole analogues and their biological evaluation

A rapid, efficient and environmental benign methodology for the preparation of 2,5-disubstituted indole analogues is developed. 2,5-Disubstituted indole-3-carboxaldehydes ( 1a– c) undergo Knoevenagel condensation with barbiturates ( 2 & 4), thiazolidine-2,4-dione ( 6) and 3-methyl-1 H-pyrazol-5(4 H)-one ( 8) in solvent-free, NH 4OAc catalyzed, microwave assisted reaction. Structures of the products thus obtained were confirmed by their m.p, Elemental analysis, IR, 1H NMR, 13C NMR and Mass spectral data. The in vitro antioxidant and cytotoxic activities against three tumor cell lines were evaluated and discussed in terms of their structural differences. Among the screened compounds 9b, 9c, 7b and 5b exhibited excellent antioxidant activity. Compounds 9b, 9c and 7b have shown strong cytotoxicity among the compounds tested.

ChemInform Abstract: Microwave‐Assisted Synthesis of Medicinally Relevant Indoles

AbstractReview: 138 refs.

Aminoalkylindoles: atypical dopamine antagonists.

The neuropharmacological profile of a series of aminoalkylindole compounds (AHR 1229-(3-[2-(3-indolyl)-ethyl]-butylamino-1-phenyl-pyrrolidine), AHR1771-(1-[2-(2-methyl-3-indolyl)ethyl]-4-phenyl-3,4-dehydropiperidine), AHR1806-(1-[2-(5-chloro-3-indolyl)-ethyl]-4-phenyl-3,4-dehydropiperidine), AHR1858-(1-[2-(3-indolyl)ethyl]-4-(4-fluorophenyl)-1,2,3, 6-tetrahydropyridine), AHR1709-(1-[2-(3-indolyl)ethyl]-4-phenyl-1,2,3,6-tetrahydropyridine) was determined in comparison with the classical neuroleptic agents haloperidol and oxypertine, the latter being of similar indole structure. The indole analogues were shown to antagonize amphetamine-induced toxicity in aggregated mice, to indicate a 'tranquillizing' action but, in contrast to haloperidol and oxypertine, showed weak or no activity in other classical behavioural tests for neuroleptic action, catalepsy induction and stereotypy antagonism. In further contrast to haloperidol or oxypertine, the indole derivatives failed to displace [3H]spiperone in radioligand binding assays and failed to increase prolactin levels. However, similarly to both typical and atypical neuroleptic agents, the indole derivatives were shown to inhibit the behavioural hyperactivity resulting from the intracerebral administration of dopamine into the mesolimbic nucleus accumbens of rat. The dissociation of an ability to antagonize a dopamine action in the mesolimbic system from classical neuroleptic actions involving other cerebral dopamine systems is the most important finding of the present study.

Antiamoebic Activity of Indole Analogues of Emetine with In-Vitro Potency Greater than that of Emetine

Antiamoebic Activity of Indole Analogues of Emetine with In-Vitro Potency Greater than that of Emetine

Design and synthesis of benzoxazole containing indole analogs as peroxisome proliferator-activated receptor-γ/δ dual agonists

A series of benzoxazole or benzothiazole containing indole analogs, 6-alkoxyindole-2-carboxylic acids and 5-alkoxy-3-indolylacetic acids, were synthesized as novel candidates of PPARγ/δ dual agonists and their ligand activities for PPAR subtypes (α, γ, and δ) were investigated. In transient transactivation assay, several compounds activated PPARγ and δ with little activity of PPARα. Putative binding mode of the compounds 1a and 2a in the active site of PPARγ was similar with that of rosiglitazone and the molecular modeling provides molecular insight to the observed activity.

Solution Structure of a Novel Heterocyclic Dication Stacked as a Dimer with a Unique Mixed GC/AT Containing Motif

The search for small-molecules that can target regulatory nucleic acid elements is an ever-growing field driven by the passion that such molecules can potentially alter gene expression and thus influence diverse cellular functions. In recent years, small-molecules preferentially binding to G•C sequences have attracted the scientific community to further understand and establish DNA base-pair recognition rules. Biophysical studies from our group have shown that DB293, a phenyl-furan-benzimidazole aromatic dication, and DB1878, an indole analog, target G•C containing sequences in a highly cooperative manner. Current high resolution NMR studies of the two compounds with 5′-CTATGACTCTCGTCATAG-3′ hairpin sequence (binding site highlighted) have confirmed a strong cooperative dimerization of the compound at the 5′-ATGA-3′ site. Strong NOE interactions between DB1878 and specific DNA protons along the minor groove indicate an anti-parallel orientation of the two molecules in the minor-groove. Very interestingly, the two DB1878 molecules recognize the ATGA sequence in what we termed as an “in-out” model, where the furan rings of the two molecules are opposite to each other. This unique stacking mode enables the furan ring of one of the molecules to recognize the guanine amino group. Mutation studies show that replacing the central G•C base-pair with any other base completely altered the binding affinity, thereby suggesting the importance of that base-pair for compound recognition. Further analyses of the complex have shown that the two DB1878 molecules stack with optimal cation-pi type interactions and with favorable van der Waals interactions along the minor groove. The structure reported here is completely different from known DNA recognition, and represents an entirely new DNA minor groove recognition paradigm. Supported by NIAID Grant AI64200.

Microwave-Assisted Synthesis of Medicinally Relevant Indoles

Indoles represent an important structural class in medicinal chemistry with broad spectrum of biological activities. The synthesis of indoles, therefore, has attracted enormous attention from synthetic chemists. Microwave methods for the preparation of indole analogs have been developed to speed up the synthesis, therefore, microwave assisted organic synthesis (MAOS) in controlled conditions is an invaluable technique for medicinal chemistry. In this review, indole forming classical reactions such as Fischer, Madelung, Bischler-Mohlau, Batcho-Leimgruber, Hemetsberger-Knittel, Graebe-Ullmann, Diels-Alder and Wittig type reactions using microwave radiation has been summarized. In addition, metal mediated cyclizations along with solid phase synthesis of indoles have been discussed.

Synthesis, Testing and Structure-Activity Studies on a Library of 5-HT4 Ligands

Several indole derivatives and analogues comprising a range of related structural classes were designed, synthesized and tested as ligands for the 5-HT₄ receptor. Within each series, binding experiments showed compounds with good affinity demonstrating high percentage displacement values at 1 µM. The most potent of these (20) had a pKi of 8.54 demonstrating very good affinity. These indole analogues were combined with 55 ligands that were previously produced in our laboratory to explore the structure-activity relationships of these 5-HT₄ ligands. A CoMFA (Comparative Molecular Field Analysis) analysis was used to extend an earlier simple pharmacophore to suggest two new molecular features beyond the primary amino binding site. The pharmacophore confirmed that a newly described tetrahydroquinoline analogue was able to match the basic requirements of the model and the pharmacology of this molecule is provided in more detail.

Acrylonitrile Quenching of Trp Phosphorescence in Proteins: A Probe of the Internal Flexibility of the Globular Fold

Quenching of Trp phosphorescence in proteins by diffusion of solutes of various molecular sizes unveils the frequency-amplitude of structural fluctuations. To cover the sizes gap between O2 and acrylamide, we examined the potential of acrylonitrile to probe conformational flexibility of proteins. The distance dependence of the through-space acrylonitrile quenching rate was determined in a glass at 77 K, with the indole analog 2-(3-indoyl) ethyl phenyl ketone. Intensity and decay kinetics data were fitted to a rate, k(r) =k0 exp[−(r −r0)/re], with an attenuation length re = 0.03 nm and a contact rate k0 = 3.6 × 1010 s−1. At ambient temperature, the bimolecular quenching rate constant (kq) was determined for a series of proteins, appositely selected to test the importance of factors such as the degree of Trp burial and structural rigidity. Relative to kq = 1.9 × 109 M−1s−1 for free Trp in water, in proteins kq ranged from 6.5 × 106 M−1s−1 for superficial sites to 1.3 × 102 M−1s−1 for deep cores. The short-range nature of the interaction and the direct correlation between kq and structural flexibility attest that in the microsecond-second timescale of phosphorescence acrylonitrile readily penetrates even compact protein cores and exhibits significant sensitivity to variations in dynamical structure of the globular fold.