Synthesis of 3,5-bis(2-indolyl)pyridine and 3-[(2-indolyl)-5-phenyl]pyridine derivatives as CDK inhibitors and cytotoxic agents

We here report the synthesis and biological evaluation of new 3,5-bis(2-indolyl)pyridine and 3-[(2-indolyl)-5-phenyl]pyridine designed as potential CDK inhibitors. Indole, 5-hydroxyindole, and phenol derivatives were used to generate three substitutions of the pyridine. The resulting skeletons were successively exploited to introduce various dimethylaminoalkyl side chains by Williamson type reactions. The synthesis includes Stille or Suzuki type reactions, which were realized on the 3,5-dibromopyridine. The preparation and the use of stannylindoles in mono or bis cross-coupling reactions were also described and each step was optimized and detailed. Kinase assays were realized and shown that nude compounds 7, 18, and 25 inhibited CDK1 in the 0.3–0.7 micromolar range with a good selectivity over GSK-3. Cytotoxicity against CEM human leukemia cells was evaluated with IC₅₀ values in the 5–15 micromolar range. Precise structure–activity relationships were delineated. Molecular modeling and docking solutions were proposed to complete the studies and to explain the observed SAR in the CDK assays.     

Design,synthesis and SAR of substituted indoles as selective TrkA inhibitors

A series of substituted indoles were examined as selective inhibitors of tropomyosin-related kinase receptor A (TrkA), a therapeutic target for the treatment of pain. An SAR optimization campaign based on ALIS screening lead compound 1 is reported.     

Substituted 3-(4-(1,3,5-triazin-2-yl)-phenyl)-2-aminopropanoic acids as novel tryptophan hydroxylase inhibitors

Tryptophan hydroxylase (TPH) is a key enzyme in the synthesis of serotonin. As a neurotransmitter, serotonin plays important physiological roles both peripherally and centrally. Here we describe the discovery of substituted triazines as a novel class of tryptophan hydroxylase inhibitors. This class of TPH inhibitors can selectively reduce serotonin levels in murine intestine after oral administration without affecting levels in the brain. These TPH inhibitors may provide novel treatments for gastrointestinal disorders associated with dysregulation of the serotonergic system, such as chemotherapy-induced emesis and irritable bowel syndrome.     

Molecular-modeling based design, synthesis, and activity of substituted piperidines as gamma-secretase inhibitors

Alzheimer's disease (AD) is a debilitating disease widely thought to be associated with the accumulation of beta amyloid (Abeta) in the brain. Inhibition of gamma-secretase, one of the enzymes responsible for Abeta production, may be a useful strategy for the treatment of AD. Described below is a series of gamma-secretase inhibitors designed from a scaffold identified by a ROCS [J. Comput. Chem.1996, 17, 1653] search of the corporate database.     

Design, synthesis, and biological evaluation of 1-(4-sulfamylphenyl)-3-trifluoromethyl-5-indolyl pyrazolines as cyclooxygenase-2 (COX-2) and lipoxygenase (LOX) inhibitors

A series of 20 novel 1-(4-sulfamylphenyl)-3-trifluoromethyl-5-indolyl pyrazolines were designed, synthesized, and screened in vitro for anti-inflammatory activity. These compounds were designed for evaluation as dual inhibitors of cyclooxygenases (COX-1 and COX-2) and lipoxygenases (LOX-5, LOX-12, and LOX-15) that are responsible for inflammation and pain. All pyrazoline molecules prepared are optically active and compounds that are more potent in COX-2 inhibitory activity (5a and 5f) were resolved by chiral column and each enantiomer was tested for cyclooxygenase inhibitory activity. Molecular modeling and comparison of molecular models of 5a enantiomers with that of celecoxib model shows that 5a (enantiomer-1) and 5a (enantiomer-2) have more hydrogen bonding interactions in the catalytic domain of COX-2 enzyme than celecoxib. Compounds 5a, 5e, and 5f showed moderate to good LOX-5 and LOX-15 inhibitory activity and this is comparable to that of celecoxib and more potent than rofecoxib.     

Core modification of substituted piperidines as Novel inhibitors of HDM2–p53 protein–protein interaction

The discovery of 3,3-disubstituted piperidine 1 as novel p53–HDM2 inhibitors prompted us to implement subsequent SAR follow up directed towards piperidine core modifications. Conformational restrictions and further functionalization of the piperidine core were investigated as a strategy to gain additional interactions with HDM2. Substitutions at positions 4, 5 and 6 of the piperidine ring were explored. Although some substitutions were tolerated, no significant improvement in potency was observed compared to 1. Incorporation of an allyl side chain at position 2 provided a drastic improvement in binding potency.     

1-[4-(1H-Benzoimidazol-2-yl)-phenyl]-3-[4-(1H-benzoimidazol-2-yl)-phenyl]-urea derivatives as small molecule heparanase inhibitors

A novel class of 1-[4-(1H-benzoimidazol-2-yl)-phenyl]-3-[4-(1H-benzoimidazol-2-yl)-phenyl]-ureas are described as potent inhibitors of heparanase. Among them are 1,3-bis-[4-(1H-benzoimidazol-2-yl)-phenyl]-urea (7a) and 1,3-bis-[4-(5,6-dimethyl-1H-benzoimidazol-2-yl)-phenyl]-urea (7d), which displayed good heparanase inhibitory activity (IC(50) 0.075-0.27 microM). Compound 7a showed good efficacy in a B16 metastasis model.     

The synthesis of substituted fluorenes as novel non-imidazole histamine h(3) inhibitors

A novel non-imidazole fluorene oxime 1a has been identified as a histamine H(3) inhibitor, and its structure-activity relationship has been evaluated.     

2- and 3-[(aryl)(azolyl)methyl]indoles as potential non-steroidal aromatase inhibitors

The present study was designed to follow our pharmacomodulation work in the field of non-steroidal aromatase inhibitors. All target compounds 12a-h and 28a-h were tested in vitro for human placental aromatase inhibition, using testosterone or androstenedione as the substrate for the aromatase enzyme and the IC50 and relative potency to aminoglutethimide data are included. A SAR study indicated that 3-[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]-1-ethyl-2-methyl-1H-indole (28 g) was a highly potent and selective aromatase inhibitor with IC50 value of 0.025 microM. 28 g was also a weak inhibitor of androstenedione synthesis.     

Synthesis and activity of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors

A series of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors was discovered. Several compounds such as 15 and 20 showed good hNET potency. Compounds 15 and 20 also displayed excellent selectivity at hNET that appeared superior to those of reboxetine and atomoxetine (4 and 5).     

Design, synthesis and utilization of 1- substituted sulphonyloxy-2-phenyl benzimidazole as a novel peptide coupling reagents

Highly efficient coupling reagents, N-methanesulphonyloxy-2-phenyl benzimidazole and N - p-toluenesulphonyloxy-2-phenyl benzimidazole were designed, synthesized and successfully applied in peptide coupling reactions. Their efficiency was evaluated by synthesizing a number of structurally different amides and peptides as well. The distereomeric purity was examined by HPLC. Also the optical rotations of all the synthesized peptides were measured and found to be quite matching with corresponding values in literature. After completion of reaction, the N-hydroxy 2-phenyl benzimidazole which was the starting material for the synthesis of reagents could be easily isolated during the work up by acid base treatment and could be re-used without significant loss in reactivity. Also the intermediate in the reaction sequence was isolated and characterized by mass and (1)H NMR which could help to comment about the probable mechanism.     

Cyclization of N[2-(3-indolyl)acetyl]-5-aminovaleraldehydes and N[2-(3-indolyl)ethyl]-5-aminovaleraldehydes

Various model cyclizations related to the organic or biological synthesis of diverse indole alkaloids, are described and discussed, including: 18 → 20, 23 → 25, 28 → 31 and 29 → 35, 37, 38 and 39 (as aldehydes).     

Synthesis and biological evaluation of 2,5-di(7-indolyl)-1,3,4-oxadiazoles,and 2- and 7-indolyl 2-(1,3,4-thiadiazolyl)ketones as antimicrobials

A range of novel hydrazine bridged bis-indoles was prepared from readily available indole-7-glyoxyloylchlorides and 7-trichloroacetylindoles and underwent cyclodehydration to produce 2,5-di(7-indolyl)-1,3,4-oxadiazoles and a 2,2′-bi-1,3,4-oxadiazolyl with phosphoryl chloride in ethyl acetate. This efficient protocol was subsequently used for the synthesis of 2- and 7-indolyl 2-(1,3,4-thiadiazolyl)ketones from related indolyl-hydrazine carbothioamides. The synthesised bis-indoles were evaluated for their antimicrobial properties, particularly the inhibition of protein–protein complex formation between RNA polymerase and σ factor and their bactericidal effect on Gram positive Bacillus subtilis and Gram negative Escherichia coli.     

Discovery of N-(3-(morpholinomethyl)-phenyl)-amides as potent and selective CB2 agonists

Recently sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Replacing the sulfonamide functionality and reversing the original carboxamide bond led to the discovery of N-(3-(morpholinomethyl)-phenyl)-amides as potent and selective CB₂ agonists. Selective CB₂ agonist 31 (K_i = 2.7; CB₁/CB₂ = 190) displayed robust activity in a rodent model of postoperative pain.     

Design and synthesis of indolo[2,3-a]quinolizin-7-one inhibitors of the ZipA-FtsZ interaction

The binding of FtsZ to ZipA is a potential target for antibacterial therapy. Based on a small molecule inhibitor of the ZipA-FtsZ interaction, a parallel synthesis of small molecules was initiated which targeted a key region of ZipA involved in FtsZ binding. The X-ray crystal structure of one of these molecules complexed with ZipA was solved. The structure revealed an unexpected binding mode, facilitated by desolvation of a loosely bound surface water.     

Structure and activity relationship of 2-(substituted benzoyl)-hydroxyindoles as novel CaMKII inhibitors

A series of novel 2-substituted-5-hydroxyindoles were synthesized and evaluated for their inhibitory activity against CaMKII. Structure and activity relationship results indicated that potent inhibitory activity could be achieved by modification at the para-position of the phenyl ring of the high throughput screening hit compound 2. Among the prepared compounds, we identified 14 as a novel CaMKII inhibitor with an activity stronger than that of KN-93, a known CaMKII inhibitor.     

Conformationally restricted homotryptamines. Part 5: 3-(trans-2-aminomethylcyclopentyl)indoles as potent selective serotonin reuptake inhibitors

A series of racemic 3-(trans-2-aminomethylcyclopentyl)indoles was synthesized and found to have potent binding to the human serotonin transporter (hSERT). The most active analog was synthesized stereospecifically and the active enantiomer was shown to have high affinity binding to hSERT.     

Design, synthesis and biological evaluation of 2-(substituted phenyl)thiazolidine-4-carboxylic acid derivatives as novel tyrosinase inhibitors

Herein we describe the design, synthesis and biological activities of 2-(substituted phenyl)thiazolidine-4-carboxylic acid derivatives as novel tyrosinase inhibitors. The target compounds 2a–2j were designed and synthesized from the structural characteristics of N-phenylthiourea, tyrosinase inhibitor and tyrosine, and l-DOPA, the natural substrates of tyrosinase. Among them, (2R/S,4R)-2-(2,4-dimethoxyphenyl)thiazolidine-4-carboxylic acid (2g) caused the greatest inhibition 66.47% at 20 μM of l-DOPA oxidase activity of mushroom tyrosinase. Kinetic analysis of tyrosinase inhibition revealed that 2g is a competitive inhibitor. We predicted the tertiary structure of tyrosinase, and simulated the docking of mushroom tyrosinase with 2g. These results suggest that the binding affinity of 2g with tyrosinase is high. Also, 2g effectively inhibited tyrosinase activity and reduced melanin levels in B16 cells treated with α-MSH. These data strongly suggest that 2g can suppress the production of melanin via the inhibition of tyrosinase activity.     

The discovery of substituted 4-(3-hydroxyanilino)-quinolines as potent RET kinase inhibitors

Substituted 4-(3-hydroxyanilino)-quinoline compounds, initially identified as small-molecule inhibitors of src family kinases, have been evaluated as potential inhibitors of RET kinase. Three compounds, 38, 31, and 40, had K(i)'s of 3, 25, and 50 nM in an in vitro kinase assay; while a cell based kinase assay showed K(i)'s of 300, 100, and 45 nM, respectively. These compounds represent potential new leads for the treatment of medullary and papillary thyroid cancer.