Synthesis and evaluation of 3-(benzylthio)-5-(1H-indol-3-yl)-1,2,4-triazol-4-amines as Bcl-2 inhibitory anticancer agents

A series of substituted 3-(benzylthio)-5-(1H-indol-3-yl)-4H-1,2,4-triazol-4-amines has been synthesised and tested in vitro as potential pro-apoptotic Bcl-2-inhibitory anticancer agents. Synthesis of the target compounds was readily accomplished in good yields through a cyclisation reaction between indole-3-carboxylic acid hydrazide and carbon disulfide under basic conditions, followed by S-benzylation. Active compounds, such as the nitrobenzyl analogue 6c, were found to exhibit sub-micromolar IC₅₀ values in Bcl-2 expressing human cancer cell lines. Molecular modelling and ELISA studies further implicated anti-apoptotic Bcl-2 as a candidate molecular target underpinning anticancer activity.     

Pim kinase inhibitory and antiproliferative activity of a novel series of meridianin C derivatives

A novel series of meridianin C derivatives substituted at C-5 position were prepared. These derivatives were tested for their kinase inhibitory potencies against all three family members of the pim kinases (Pim-1, Pim-2 and Pim-3). In addition, their antiproliferative activity towards three human leukemia cell lines as MV4-11, Jurkat clone E6-1 and K562 has been evaluated. Structure activity relationships at C-3 and C-5 positions of indole were performed to better understand the mechanism behind the enhanced potency. Compound 7f, the most active compound of the series showed a single-digit nanomolar IC₅₀ with selectivity towards Pim-1 kinase.     

Pentafluorophenyl Substitution of Natural Di(indol‐3‐yl)methane Strongly Enhances Growth Inhibition and Apoptosis Induction in Various Cancer Cell Lines

Di(indol‐3‐yl)methane (=3,3′‐methanediyldi(1H‐indole), DIM, 1 ) is a known weakly antitumoral compound formed by digestion of indole‐3‐carbinol (=1H‐indol‐3‐ylmethanol), an ingredient of various Brassica vegetables. Out of a series of nine fluoroaryl derivatives of 1 , three pentafluorophenyl derivatives 2c , 2h , and 2i were identified that exhibited a two to five times greater anti‐proliferative effect and an increased apoptosis induction when compared with 1 in the following carcinoma cell lines: BxPC‐3 pancreas, LNCaP prostate, C4‐2B prostate, PC3 prostate and the triple‐negative MDA‐MB‐231 breast carcinoma. Compound 2h was particularly efficacious against androgen‐refractory C4‐2B prostate cancer cells (IC₅₀=6.4 μm ) and 2i against androgen‐responsive LNCaP cells (IC₅₀=6.2 μm ). In addition, 2c and 2h exhibited distinct activity in three cancer cell lines resistant to 1 .     

Regioselectivity of Larock Indole Synthesis Using Functionalized Alkynes

Regioselectivity of Larock indole synthesis, a palladium-catalyzed heteroannulation between o-iodoaniline and internal acetylene, was estimated using acetylenes substituted with ester and/or Boc-protected amine at the homopropargylic position and with perbenzyl- and unprotected glucose. Low to moderate regioselectivities were observed in all the cases, indicating these functional groups do not exert good directing effects, in the Larock indole synthesis.     

Fluoranthene degradation in Pseudomonas alcaligenes PA-10

Pseudomonas alcaligenes strain PA-10 degrades thefour-ring polycyclic aromatic hydrocarbon fluoranthene, co-metabolically. HPLC analysisof the growth medium identified four intermediates, 9-fluorenone-1-carboxylicacid; 9-hydroxy-1-fluorene carboxylic acid; 9-fluorenone and 9-fluorenol, formedduring fluoranthene degradation. Pre-exposure of PA-10 to 9-fluorenone-1-carboxylic acidand 9-hydroxy-1-fluorene-carboxylic acid resulted inincreases in fluoranthene removal, while pre-exposure to9-fluorenone and 9-fluorenol resulted in a decrease influoranthene degradation. The rate of indole transformation was similarly affected by pre-exposureto these metabolic intermediates, indicating a link between fluoranthenedegradation and indigo formation in this strain.     

Analogues of Azepinomycin as Inhibitors of Guanase

Abstract

Synthesis and biochemical screening against guanase of analogues of the naturally occurring guanase inhibitor azepinomycin (2) are reported. Compound e-amino-5,6,7,8,-tetrahydro-4H-imidazo[4,5-e][1,4]diazepine-5,8-dione (3) was synthesized in six steps commencing with 1-benzyl-5-nitroimidazole-4-carboxylic acid (5). Compound 3 and its synthetic precursor 3-benzyl-6-(N-benzyloxycarbonyl)amino-5,6,7,8-tetrahydro-4H-imidazo[4,5-e][1,4]diazepine-5,8-dione (12) were screened against rabbit liver guanase. Both were found to be moderate inhibitors of the enzyme with K₁′s in the range of 10^?4 M.     

Design,Synthesis, and Fungicidal Activities of Indole-Modified Cinnamamide Derivatives

Dimethomorph is a kind of cinnamamide fungicide with high fungicidal activities for oomycete diseases. The commercially available dimethomorph is a mixture of two isomers, in which (Z)-dimethomorph possessing higher activity and (E)-dimethomorph possessing lower activity. Herein, we reported the design, synthesis and fungicidal activities of a series of novel indole-modified cinnamamide derivatives, which used the indole group to ‘fix’ the cis-styrene group in (Z)-dimethomorph. The modification of the molecular structure of cinnamamide compounds could be beneficial to improve its practical application performance. Tested the fungicidal activities, it was found that compounds 8j , 9a , 9e , 9i and 9j showed excellent in vivo fungicidal activities (80–100 %) against Pseudoperonospora cubensis at a concentration of 100 mg L⁻¹, while dimethomorph and flumorph were noneffective. Moreover, parts of synthesized indole-modified cinnamamide derivatives 8 ( 8a , 8c , 8d and 8j ) and 9 ( 9c and 9j ) exhibited the same in vivo fungicidal activities against Phytophthora infestans with dimethomorph or flumorph at a concentration of 50 mg L⁻¹ with 100 % inhibition. The biological assay results indicated that indole-modified cinnamamide derivatives have promising applications in the prevention and treatment of Phytophthora infestans.     

Design,Synthesis, and Insecticidal Activities of Novel N-Pyridylpyrazole Amide Derivatives Containing a Maleimide

To discover ‘me-better’ insecticidal active molecules targeting ryanodine receptors (RyRs), a series of novel N-pyridylpyrazole amide derivatives containing a maleimide were designed and synthesized in accordance with the prior investigations of our group. Preliminary bioassay findings indicated some compounds containing a maleimide exhibited good larvicidal activities against lepidopteran pests at a concentration of 500 mg L⁻¹. Compound 9 j showed 60 % larvicidal activities against M. Separata at 50 mg L⁻¹. Compound 9 b exhibited 40 % larvicidal activities against P. xylostella at 50 mg L⁻¹. Molecular docking study indicated that H-bonds, π–π interaction and cation-π interaction made for the binding of compounds 9 b , 9 j with P. Xylostella RyR. These results indicated that compounds 9 b and 9 j could be developed as novel and promising insecticidal leads.     

Formicidal activity of indole derivatives on Atta opaciceps (Borgmeier): Lethal,behavioural and locomotive effects

The leaf‐cutting ants of the genus Atta are of extreme importance for agriculture and forestry. Few active products can be employed to control these pests and, therefore, the discovery of new insecticidal products represents a fundamental strategy for its management. In this study, we evaluated the mortality, behaviour and locomotion of workers of Atta opaciceps (Borgmeier) exposed to synthesized indole derivatives. The most active compound was 4d [1‐(1H‐indol‐3‐yl)pentan‐1‐one] (LD₅₀ = 0.018 μg/mg), while the 4e [1‐(1H‐indol‐3‐yl)hexan‐1‐one] (LD₅₀ = 3.82 μg/mg) was the least active compound. These two derivatives reduced the survival of A. opaciceps over time and altered the behaviour and locomotion of these ants. This study demonstrates the potential of indole derivatives to produce new formicidal products, since, in addition to being effective, it also affects the ant's behaviour and locomotion.     

Two New Prenylated Indole Diterpenoids from Tolypocladium sp. and Their Antimicrobial Activities

Two new prenylated indole diterpenoids, tolypocladins K and L ( 1 and 2 ), together with a known analog terpendole L ( 3 ), were isolated from the solid fermentation culture of a mine soil‐derived fungus Tolypocladium sp. XL115. Their structures and relative configurations were determined by comprehensive spectroscopic data analysis, as well as by comparison of their NMR data with those related known compounds. Compound 3 exhibited remarkable antibacterial activity against Micrococcus luteus with an MIC value of 6.25 μg/mL, and compounds 1 and 3 displayed moderate antifungal activity selectively against tested strains with MIC values of 25–50 μg/mL.     

Synthesis and evaluation of in vitro antiviral activity of 2-[3-(substituted phenyl)-4,5-dihydro-1H-5-pyrazolyl]benzofuran-3-yl chloride derivatives

3-Chlorobenzofuran-2-carbaldehyde was condensed with substituted acetophenone by using the Claisen-Schmidt condensation to obtain 3-(3-chlorobenzofuran-2-yl)-1-(substituted phenyl)-2-propen-1-one (2a-m) which upon further treatment with hydrazine hydrate gave 2-[3-(substituted phenyl)-4,5-dihydro-1H-5- pyrazolyl)benzofuran-3-yl chloride derivatives (3a-m). All the newly synthesized derivatives were evaluated in vitro for cytotoxicity and antiviral activity in Crandell-Rees Feline Kidney cell, human embryonic lung (HEL) cell, HeLa cell and Vero cell cultures against different viruses. Several compounds, i.e. 2f, 2g, 2i, 2m, 3b, 3d, 3g, 3h and 3m proved quite cytotoxic to the host cells (minimum cytotoxic concentration: 1-10 μg/mL). No specific antiviral activity [50% antivirally effective concentration (EC₅₀) ≥ 5-fold lower than the minimum cytototoxic concentration] was observed for any of the compounds.     

Retinoic Acid Metabolism Inhibition by 3-Azolylmethyl-1H-indoles and 2, 3 or 5-(α-Azolylbenzyl)-1H-indoles

Among a library of 70 azoles, 8 indole derivatives substituted in the 2-, 3- or 5- position with an azolylmethyl or α-azolylbenzyl chain were evaluated for retinoic acid (RA) metabolism inhibitory activity. The most active inhibitors identified in this study were 5-bromo-1-ethyl-3-methyl-2-[(phenyl)(1H-1,2,4-triazol-1-yl)methyl]-1H-indole (3) (68.9% inhibition) and 5-bromo-1-ethyl-2-[(4-fluorophenyl)(1H-1,2,4-triazol-1-yl)methyl]-3-methyl-1H-indole (6) (60.4% inhibition). At the same concentration (100 μM) ketoconazole exerted similar inhibitory effect (70% inhibition).     

β-Carboline-Based pH Fluorescent Probe and Its Application for Monitoring Enzymatic Ester Hydrolysis

A novel pH-activatable fluorescent probe, 1-(propan-2-yl)-9H-pyrido[3,4-b]indole-3-carboxylic acid ( L-1 ), based on β-carboline derivatives, has been developed, which displays significant fluorescent response toward pH variation with high selectivity, good photo-stability and favorable pKa value. Moreover, L-1 can dynamically monitor the release of protons during ester hydrolysis reaction in consistent with enzymatic kinetics manner.     

Design,synthesis, in vitro antiproliferative activity and apoptosis-inducing studies of 1-(3′,4′,5′-trimethoxyphenyl)-3-(2′-alkoxycarbonylindolyl)-2-propen-1-one derivatives obtained by a molecular hybridisation approach

Inhibition of microtubule function using tubulin targeting agents has received growing attention in the last several decades. The indole scaffold has been recognized as an important scaffold in the design of novel compounds acting as antimitotic agents. Indole-based chalcones, in which one of the aryl rings was replaced by an indole, have been explored in the last few years for their anticancer potential in different cancer cell lines. Eighteen novel (3′,4′,5′-trimethoxyphenyl)-indolyl-propenone derivatives with general structure 9 were synthesized and evaluated for their antiproliferative activity against a panel of four different human cancer cell lines. The highest IC₅₀ values were obtained against the human promyelocytic leukemia HL-60 cell line. This series of chalcone derivatives was characterized by the presence of a 2-alkoxycarbonyl indole ring as the second aryl system attached at the carbonyl of the 3-position of the 1-(3′,4′,5′-trimethoxyphenyl)-2-propen-1-one framework. The structure–activity relationship (SAR) of the indole-based chalcone derivatives was investigated by varying the position of the methoxy group, by the introduction of different substituents (hydrogen, methyl, ethyl or benzyl) at the N-1 position and by the activity differences between methoxycarbonyl and ethoxycarbonyl moieties at the 2-position of the indole nucleus. The antiproliferative activity data of the novel synthesized compounds revealed that generally N-substituted indole analogues exhibited considerably reduced potency as compared with their parent N-unsubstituted counterparts, demonstrating that the presence of a hydrogen on the indole nitrogen plays a decisive role in increasing antiproliferative activity. The results also revealed that the position of the methoxy group on the indole ring is a critical determinant of biological activity. Among the synthesized derivatives, compound 9e, containing the 2-methoxycarbonyl-6-methoxy-N-1H-indole moiety exhibited the highest antiproliferative activity, with IC₅₀ values of 0.37, 0.16 and 0.17?μM against HeLa, HT29 and MCF-7 cancer cell lines, respectively, and with considerably lower activity against HL-60 cells (IC₅₀: 18?μM). This derivative also displayed cytotoxic properties (IC₅₀ values ～1?μM) in the human myeloid leukemia U-937 cell line overexpressing human Bcl-2 (U-937/Bcl-2) via cell cycle progression arrest at the G₂-M phase and induction of apoptosis. The results obtained also demonstrated that the antiproliferative activity of this molecule is related to inhibition of tubulin polymerisation. The presence of a methoxy group at the C5- or C6-position of the indole nucleus, as well as the absence of substituents at the N-1-indole position, contributed to the optimal activity of the indole-propenone-3′,4′,5′-trimethoxyphenyl scaffold.     

First Synthesis of Double Headed 1,3,4‐Oxadiazino[6,5‐b]indole Acyclo C‐Nucleosides

Condensation of 1,3‐dihydro‐2,3‐dioxo‐2H‐indoles (1a–c) with galactaric acid bis hydrazide (2) gave the corresponding galactaric acid bis[2‐(1,2‐dihydro‐2‐oxo‐3H‐indol‐3‐ylidene)hydrazides] (3a–c). Acetylation of the latter compounds with acetic anhydride in the presence of pyridine at ambient temperature gave the 2,3,4,5‐tetra‐O‐acetylgalactaric acid bis[2‐(1,2‐dihydro‐2‐oxo‐1‐substituted‐3H‐indol‐3‐ylidene)hydrazides] (4b–d). Heterocyclization of the tetra‐O‐acetates 4b–d by heating with thionyl chloride afforded the double headed acyclo C‐nucleosides: 1,2,3,4‐tetra‐O‐acetyl‐1,4‐bis{9‐substituted‐1,3,4‐oxadiazino[6,5‐b]indol‐2‐yl‐1‐ium}‐galacto‐tetritol dichlorides (5b–d). Structures of the prepared compounds were elucidated from their spectral properties.     

Synthesis and PreliminaryIn Vitro Evaluation of Antimycobacterial Activity of New Pyrrolo[1,2-a]quinoxaline-carboxylic Acid Hydrazide Derivatives

New pyrrolo[1,2-a]quinoxaline-2- or -4-carboxylic acid hydrazide derivatives were synthesized from nitroaniline or 1,2-phenylenediamine, and evaluated in vitro for their antimycobacterial activity as part of a TAACF TB screening program. Two compounds 7c and 13 showed an interesting activity at 6.25?μg/mL against Mycobacterium tuberculosis H₃₇Rv, with a 94 and 100 percentage inhibition, respectively.     

Synthesis and Antiviral Evaluation of Some Novel Tricyclic Pyrazolo[3,4‐b]indole Nucleosides

Novel pyrazolo[3,4‐b]indole nucleoside analogs were synthesized from the corresponding 3‐formyl‐2‐chloroindole and 3‐cyano‐2‐chloroindole nucleosides by treatment with hydrazine. Very few examples of pyrazolo[3,4‐b]indole heterocycles have been published in the literature and this is the first synthesis of nucleoside analogs containing this heterocycle. These new pyrazolo[3,4‐b]indole nucleosides were active against human cytomegalovirus and herpes simplex virus type 1, but this activity was not well separated from cytotoxicity.     

Carbazolothiophene-2-carboxylic acid derivatives as endothelin receptor antagonists

The SmI(2)-promoted three-component coupling reaction of thiophene-2-carboxylate, indole-2-carbaldehyde and acetophenone provides an expedient route to a series of tetracyclic carbazolothiophene compounds bearing the indole and thiophene rings. Among these samples, 9-benzyl-4-methyl-4-(4-hydroxyphenyl)-10-oxo-4,10-dihydrocarbazolo[2,3-b]thiophene-2-carboxylic acid (18) shows the most potent inhibition against the endothelin-1 induced increase of intracellular calcium ion concentration.     

Discovery and SAR of indole-2-carboxylic acid benzylidene-hydrazides as a new series of potent apoptosis inducers using a cell-based HTS assay

A series of indole-2-carboxylic acid benzylidene-hydrazides has been identified as a new class of potent apoptosis inducers through a novel cell-based caspase HTS assay. The screening hit, 5-chloro-3-methyl-indole-2-carboxylic acid (4-nitrobenzylidene)-hydrazide (3a), was found to arrest T47D cells in G(2)/M and to induce apoptosis as measured by the flow cytometric analysis assay. A SAR study was carried out by modification of the substitutions on the indole and benzene rings. Substitution at the 3-position of the indole ring was found to be important for apoptotic activity. A 20-fold increase of apoptotic activity was achieved from screening hit 3a to 5-methyl-3-phenyl-indole-2-carboxylic acid (4-methylbenzylidene)-hydrazide (9a) and 5-chloro-3-phenyl-indole-2-carboxylic acid (4-nitrobenzylidene)-hydrazide (9b), with EC(50) value of 0.1microM in the caspase activation assay in T47D breast cancer cells. Compound 9b also was found to be highly active in a standard growth inhibition assay with a GI(50) value of 0.9microM in T47D cells. Compound 3a and its analogs were found to inhibit tubulin polymerization, which is the most probable primary mechanism of action of these compounds.     

A convenient synthesis and molecular modeling study of novel pyrazolo[3,4-d]pyrimidine and pyrazole derivatives as anti-tumor agents

Abstract

An efficient method to obtain ethyl 5-amino-1-tosyl-1H-pyrazole-4-carboxylate (3) was outlined using condensation reactions of 4-methylbenzenesulfonylhydrazide with (E)-ethyl 2-cyano-3-ethoxyacrylate. The cyclocondensation reaction of this substrate and its hydrazide derivative with urea, thiourea, formamide, formic acid, d-glucose, o-phenylenediamine, 4-dimethylaminobenzaldehyde, anthracene-9-carbaldehyde, thioglycolic acid and carbon disulphide then with hydrazine hydrate analogues furnished a series of pyrazolo[3,4-d]pyrimidine, pyrazolo[3,4-d]oxazin-4-one, pyrazole-4-glucoside, 4-benzo[d]imidazole, 1,3-thiazolidinone, 1,3,4-oxadiazol-2(3H)-thione and 1,2,4-triazol-5(4H)-thione derivatives respectively. The structure of the compound 3 was supported by X-Ray crystallographic data. Orally administrated, one of each of the series of pyrazoles showed significant effects in mouse tumor model cancer cell lines (EAC) and two human cancer cell lines of Colon cancer (HCT-29) and Breast cancer (MCF-7) with docking studies.