Synthesis of (Z)-3-(arylamino)-1-(3-phenylimidazo[1,5-a]pyridin-1-yl)prop-2-en-1-ones as potential cytotoxic agents

The new derivatives based on (Z)-3-(arylamino)-1-(3-phenylimidazo[1,5-a]pyridin-1-yl)prop-2-en-1-one scaffold was synthesized and evaluated for their in vitro cytotoxic potential against a panel of cancer cell lines, viz., A549 (human lung cancer), HCT-116 (human colorectal cancer), B16F10 (murine melanoma cancer), BT-474 (human breast cancer), and MDA-MB-231 (human triple-negative breast cancer). Among them, many of the synthesized compounds exhibited promising cytotoxic potential against the panel of tested cancer cell lines with IC₅₀ <30 µM. Based on the preliminary screening results, the structure-activity relationship (SAR) of the compounds was established. Among the synthesized compounds, 15i displayed a potential anti-proliferative activity against HCT-116 cancer cell line with an IC₅₀ value of 1.21 ± 0.14 µM. Flow cytometric analysis revealed that compound 15i arrested the G0/G1 phase of the cell cycle. Moreover, increased reactive oxygen species (ROS) generation, clonogenic assay, acridine orange staining, DAPI nuclear staining, measurement of mitochondrial membrane potential (ΔΨm), and annexin V-FITC assays revealed that compound 15i promoted cell death through apoptosis.     

Synthesis and antibacterial activity of 7-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl) quinolones

A novel series of 7-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl) quinolones has been designed and synthesized in which the heterocyclic side chain is attached to the quinolone core through a carbon–carbon linkage. The antibacterial activity of the compounds was determined against a panel of Gram-positive and Gram-negative pathogens. Compounds 1b and 1e, bearing an 8-methoxy group as well as unsubstituted and (3S)-methyl substituted 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl side chains, respectively, demonstrated notable activity against ciprofloxacin-resistant clinical isolates of Streptococcus pneumoniae.     

Luminescence of imidazo[1,2-a]pyrazin-3(7H)-one compounds

In this review I will discuss chemical principles of the luminescence of imidazo[1,2-a]pyrazin-3(7H)-one compounds described to date. The review is composed of two main parts, the first dealing with the bioluminescence of coelenterate luciferin “coelenterazine” and Cypridina luciferin in marine organisms and the second with the chemiluminescence of these luciferins and their analogues. In the second section, possible applications of chemiluminescence and enhanced chemiluminescence in the area of bioassay are also discussed.     

Synthesis and antitrichinellosis activity of some 2-substituted-[1,3]thiazolo[3,2-a]benzimidazol-3(2H)-ones

Some new thiazolo[3,2-a]benzimidazolone derivatives were synthesized using two methods. The structures of the synthesized compounds were proved by means of IR, (1)H NMR and mass spectral data. Ab initio computations were performed in order to determine the electronic structure and geometry of the investigated molecules and to compare it to the geometry of albendazole. Biologically, experiments in vitro and in vivo were accomplished in order to identify the efficacy of the obtained thiazolobenzimidazolones against Trichinella spiralis. The effectiveness of compounds 4a-c in the intestinal phase of trichinellosis was 100% and in the muscle phase were 88% and 80% at a concentration of 100mg/kg mw for the compounds 4a and 4c. The results of the hepatotoxicity test showed that the compounds 4a and 4b possess hepatotoxicity comparable to that of albendazole.     

Synthesis of 3-(1H-benzimidazol-2-yl)-5-isoquinolin-4-ylpyrazolo[1,2-b]pyridine, a potent cyclin dependent kinase 1 (CDK1) inhibitor

The novel compound 3-(1H-benzimidazol-2-yl)-5-isoquinolin-4-ylpyrazolo[1,2-b]pyridine was discovered to be a potent CDK1 inhibitor. Described here is the chemistry for its synthesis, including Pd(II) catalyzed Stille coupling reaction and sulfur(0) induced benzimidazole formation. Its effects on VEGFR-2 kinase activity and tumour cell proliferation are also described.     

8-Hydroxy-3,4-dihydropyrrolo[1,2-a]pyrazine-1(2H)-one HIV-1 integrase inhibitors

A series of potent novel 8-hydroxy-3,4-dihydropyrrolo[1,2-a]pyrazine-1(2H)-one HIV-1 integrase inhibitors was identified. These compounds inhibited the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 12 is active against replication of HIV-1 in cell culture with a CIC(95) of 0.31microM. Further SAR exploration led to the preparation of pseudosymmetrical tricyclic pyrrolopyrazine inhibitors 23 and 24 with further improvement in antiviral activity.     

Synthesis and antibacterial activity of 1-[1,2,4-triazol-3-yl] and 1-[1,3,4-thiadiazol-2-yl]-3-methylthio-6,7-dihydrobenzo[c]thiophen-4(5H)ones

A series of 1-[1,2,4-triazol-3-yl] and 1-[1,3,4-thiadiazol-2-yl]-3-methylthio-6,7-dihydrobenzo[c]thiophen-4(5H)ones were synthesized and tested to demonstrate in vitro antimicrobial activity. Some of these compounds exhibited a good activity against Staphylococcus aureus, S. epidermidis and Bacillus subtilis.     

Synthesis and biological evaluation of the metabolites of 2-(1-{3-[(6-chloronaphthalen-2-yl)sulfonyl]propanoyl}piperidin-4-yl)-5-methyl-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one

We have recently discovered imidazo[1,5-c]imidazol-3-one derivative 1 as a potent, selective, and orally bioavailable factor Xa (FXa) inhibitor. In this study, we have synthesized metabolites of 1 and evaluated their biological activities. As a result, we identified the active metabolites S-5 and 6 with a potent FXa inhibitory activity comparable to 1 and a favorable pharmacokinetic profile in monkeys.     

Synthesis of N-(1-methyl-1H-indol-3-yl)methyleneamines and 3,3-diaryl-4-(1-methyl-1H-indol-3-yl)azetidin-2-ones as potential antileishmanial agents

A series of N-(1-methyl-1H-indol-3-yl)methyleneamines and eight new 3,3-diaryl-4-(1-methyl-1H-indol-3-yl)azetidin-2-ones have been synthesized and screened for their antileishmanial activity against Leishmania major. 3,3-Diaryl-4-(1-methyl-1H-indol-3-yl)azetidin-2-ones have been synthesized by the Staudinger's ketene-imine cycloaddition employing two 2-diazo-1,2-diarylethanones as the precursors of diarylketenes. A marked improvement in anti-parasitic activity is observed by transformation of the methyleneamines to azetidin-2-ones in seven out of eight compounds. Two compounds displayed antileishmanial activity comparable to that of the clinically used antileshmanial drug, amphotericine B.     

Synthesis and antibacterial activity of a new series of 3-[3-(substituted phenyl)-1-phenyl-1H-pyrazol-5-yl]-2H-chromen-2-one derivatives

A series of 3-[3-(substituted phenyl)-1-phenyl-1H-pyrazol-5-yl]-2H-chromen-2-one (4a–k) were synthesized by reaction of 3-[2,3-dibromo-3-(substituted phenyl)propanoyl]-2H-chromen-2-one (3 a-k) with phenyl hydrazine in presence of triethylamine in absolute ethanol, characterized by spectral data and screened for their in vitro antibacterial activity against gram-positive and gram-negative bacteria. Among the series, compounds 4d, 4h and 4i displayed an encouraging antibacterial activity profile as compared to reference standard drug ciprofloxacin against tested bacterial strains.     

Novel (E)-1-(4-methyl-2-(alkylamino)thiazol-5-yl)-3-arylprop-2-en-1-ones as potent antimicrobial agents

New (E)-1-(4-methyl-2-(alkylamino)thiazol-5-yl)-3-arylprop-2-en-1-ones, unsubstituted or carrying fluoro, bromo, methoxy, nitro, methyl and chloro groups on the benzene ring, were synthesized and assayed in vitro for their antimicrobial activity against Gram positive and Gram negative bacteria and fungi. The compounds were very potent towards all tested microorganisms and in most cases their activity was better than that of reference drugs.     

Synthesis and SAR of 2-(4-fluorophenyl)-3-pyrimidin-4-ylimidazo[1,2-a]pyridine derivatives as anticoccidial agents

Compounds 10a-10d and 10i are very potent inhibitors of Eimeria tenella cGMP-dependent protein kinase (0.081-0.32 nM) and are very efficacious antiparasitic agents in vivo when administered to chickens at 12.5-25 ppm levels in the feed.     

3-[Benzimidazo- and 3-[benzothiadiazoleimidazo-(1,2-c)quinazolin-5-yl]-2H-chromene-2-ones as potent antimicrobial agents

A series of 3-[benzimidazo(1,2-c)quinazolin-5-yl]-2H-chromene-2-one (6a-6f) and 3-[benzothiadiazole- imidazo(1,2-c)quinazolin-5-yl]-2H-chromene-2-one derivatives (7a-7f) that incorporate a variety of substituents at the 6- and/or 8-positions of the coumarin moieties have been synthesized utilizing cellulose sulfuric acid as an efficient catalyst under both conventional heating and microwave irradiation procedures. These analogs were evaluated for their antimicrobial activity against Bacillus subtilis, Staphylococcus aureus, Streptococcus pyogenes (Gram-positive bacteria), Escherichia Coli, Klebsiella pneumonia, Salmonella typhimurium (Gram-negative bacteria), and Aspergillus niger, Candida albicans, and Aspergillus flavus (Fungi). Two analogs, 6c (a 6,8-dichloro analog, MIC([SA]) = 2.5 μg/mL; MIC([ST]) = 2.5 μg/mL) and 7d (a 6,8-dibromo analog, MIC([ST]) = 2.5 μg/mL) were identified as potent antibacterial agents, and two analogs, 6b (a 6-bromo analog, MIC([AF]) = 10 μg/mL) and 6d (a 6,8-dibromo analog, MIC([AF]) = 15 μg/mL; MIC([CA]) = 15μg/mL), were identified as potent antifungal agents. Based on the MIC data, analogs 6b, 6c, 6d, and 7d were identified as the most potent antimicrobial agents in the series.     

Synthesis and dopaminergic activity of some E-3-(piperidin-1-yl)-1-(4-substituted phenyl)prop-2-en-1-one derivatives

A convenient route for the synthesis of some 2-propen-1-one derivatives with E isomeric configuration is described. The activity of the synthesized compounds was evaluated through behavioral studies of apomorphine-induced licking in animal models. It was demonstrated that most of the synthesized compounds showed moderate activity in inhibition of lickings, among which 6a, was the most active compound at 30 mg/kg.     

Synthesis and in vitro evaluation of N-alkyl-3-hydroxy-3-(2-imino-3-methyl-5-oxoimidazolidin-4-yl)indolin-2-one analogs as potential anticancer agents

A series of novel 3-hydroxy-3-(2-imino-3-methyl-5-oxoimidazolidin-4-yl)indolin-2-one analogs (3) have been synthesized under microwave irradiation and conventional heating methods. These analogs were evaluated for in vitro cytotoxicity against a panel of 57 human tumor cell lines. Compound 3o had GI₅₀ values of 190 nM and 750 nM against A549/ATTC non-small cell lung cancer and LOX IMVI melanoma cell lines, respectively, and both 3n and 3o exhibited GI₅₀ values ranging from 2 to 5 μM against CCRF-CEM, HL-60(TB), K-562, MOLT-4, and RPMI-8226 leukemia cell lines. These results indicate that N-4-methoxybenzyl-3-hydroxy-(2-imino-3-methyl-5-oxo-4-yl)indolin-2-one analogs may be useful leads for anticancer drug development.     

Synthesis of new 4-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]quinoxaline and 5-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]thieno[3,2-e]pyrazine derivatives,as potential bacterial multidrug resistance pump inhibitors

The synthesis of new 4-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]quinoxaline derivatives 1a-l is described in five or six steps starting from various substituted nitroanilines 2a-e. The bioisostere 5-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]thieno[3,2-e]pyrazine 1m was also prepared. The new derivatives were evaluated as efflux pump inhibitors (EPIs) in a model targeting the NorA system of Staphylococcus aureus. The antibiotic susceptibility of two strains overproducing NorA, SA-1199B and SA-1, was determined alone and in combination with the neo-synthesised compounds by the agar diffusion method and MIC determination, in comparison with reserpine and omeprazole taken as reference EPIs. A preliminary structure-activity relationship study firstly allowed to clarify the influence of the substituents at positions 7 and/or 8 of the pyrrolo[1,2-a]quinoxaline nucleus. Methoxy substituted compounds, 1b and 1g, were more potent EPIs than the unsubstituted compounds (1a and 1f), followed by chlorinated derivatives (1c-d and 1h). Moreover, the replacement of the N,N-diethylamino group (compounds 1a-e) by a bioisostere such as pyrrolidine (compounds 1f-h) enhanced the EPI activity, in contrast with the replacement by a piperidine moiety (compounds 1i-k). Finally, the pyrrolo[1,2-a]thieno[3,2-e]pyrazine compound 1m exhibited a higher EPI activity than its pyrrolo[1,2-a]quinoxaline analogue 1a, opening the way to further pharmacomodulation.     

Synthesis of new 4-[2-(alkylamino) ethylthio]pyrrolo[1,2-a]quinoxaline and 5-[2-(alkylamino) ethylthio]pyrrolo[1,2-a]thieno[3,2-e]pyrazine derivatives, as potential bacterial multidrug resistance pump inhibitors

The synthesis of new 4-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]quinoxaline derivatives la-1 is described in five or six steps starting from various substituted nitroanilines 2a-e. The bioisostere 5-[2-(alkylamino)ethylthio]pyrrolo[1,2- a]thieno[3,2-e]pyrazine 1m was also prepared. The new derivatives were evaluated as efflux pump inhibitors (EPIs) in a model targeting the NorA system of Staphylococcus aureus. The antibiotic susceptibility of two strains overproducing NorA, SA-1199B and SA-1, was determined alone and in combination with the neo-synthesised compounds by the agar diffusion method and MIC determination, in comparison with reserpine and omeprazole taken as reference EPIs. A preliminary structure-activity relationship study firstly allowed to clarify the influence of the substituents at positions 7 and/or 8 of the pyrrolo[1,2-a]quinoxaline nucleus. Methoxy substituted compounds, 1b and 1g, were more potent EPIs than the unsubstituted compounds (1a and 1f), followed by chlorinated derivatives (1c-d and 1h). Moreover, the replacement of the N,N-diethylamino group (compounds 1a-e) by a bioisostere such as pyrrolidine (compounds 1f-h) enhanced the EPI activity, in contrast with the replacement by a piperidine moiety (compounds 1i-k). Finally, the pyrrolo[1,2-a]thieno[3,2-e]pyrazine compound 1m exhibited a higher EPI activity than its pyrrolo[1,2-a]quinoxaline analogue la, opening the way to further pharmacomodulation.     

Inhibition of mammalian target of rapamycin signaling by 2-(morpholin-1-yl)pyrimido[2,1-alpha]isoquinolin-4-one

Signaling through the mammalian target of rapamycin (mTOR) is hyperactivated in many human tumors, including hamartomas associated with tuberous sclerosis complex (TSC). Several small molecules such as LY294002 inhibit mTOR kinase activity, but they also inhibit phosphatidylinositol 3-kinase (PI3K) at similar concentrations. Compound 401 is a synthetic inhibitor of DNA-dependent protein kinase (DNA-PK) that also targets mTOR but not PI3K in vitro (Griffin, R. J., Fontana, G., Golding, B. T., Guiard, S., Hardcastle, I. R., Leahy, J. J., Martin, N., Richardson, C., Rigoreau, L., Stockley, M., and Smith, G. C. (2005) J. Med. Chem. 48, 569-585). We used 401 to test the cellular effect of mTOR inhibition without the complicating side effects on PI3K. Treatment of cells with 401 blocked the phosphorylation of sites modified by mTOR-Raptor and mTOR-Rictor complexes (ribosomal protein S6 kinase 1 Thr(389) and Akt Ser(473), respectively). By contrast, there was no direct inhibition of Akt Thr(308) phosphorylation, which is dependent on PI3K. Similar effects were also observed in cells that lack DNA-PK. The proliferation of TSC1-/- fibroblasts was inhibited in the presence of 401, but TSC1+/+ cells were resistant. In contrast to rapamycin, long-term treatment of TSC1-/- cells with 401 did not up-regulate phospho-Akt Ser(473). Because increased Akt activity promotes survival, this may explain why the level of apoptosis was increased in the presence of 401 but not rapamycin. These results suggest that mTOR kinase inhibitors might be more effective than rapamycins in controlling the growth of TSC hamartomas and other tumors that depend on elevated mTOR activity.