Selenocyanates and diselenides: a new class of potent antileishmanial agents

Thirty five selenocyanate and diselenide compounds were subjected to in vitro screening against Leishmania infantum promastigotes and the most active ones were also tested in an axenic amastigote model. In order to establish the selectivity indexes (SI) the cytotoxic effect of each compound was also assayed against Jurkat and THP-1 cell lines.Thirteen derivatives exhibit better IC₅₀ values than miltefosine and edelfosine. Bis(4-aminophenyl)diselenide exhibits the best activity when assayed in infected macrophages and one of the lowest cytotoxic activities against the human cell lines tested, with SI values of 32 and 24 against Jurkat and THP-1 cells, respectively. This compound thus represents a new lead for further studies aimed at establishing its mechanism of action.     

Antileishmanial agents part-IV: synthesis and antileishmanial activity of novel terpenyl pyrimidines

Some novel N- and O-substituted terpenyl pyrimidines 4 (a-j) have been synthesized and screened for in vitro antileishmanial activity profile in promastigote model. Some of the compounds exhibited 100% inhibition at 10 microg ml(-1) concentration.     

Syntheses of new substituted triazino tetrahydroisoquinolines and beta-carbolines as novel antileishmanial agents

A series of triazino tetrahydroisoquinolines (3-5) and beta-carboline derivatives (15-27) have been synthesized as novel antileishmanial agents. Among them, compounds 15, 16 and 25 have shown 78.0%, 78.6% and 68.0% in vivo inhibition against Leishmania donovani at a dose of 50 mg kg(-1) x 5 days, respectively, while compounds 3 and 18 exhibited 55.6% and 53.3% in vivo inhibitions, respectively, against L. donovani at a dose of 50 mg kg(-1) x 5 days.     

4-anilinoquinoline triazines: a novel class of hybrid antimalarial agents

A novel class of hybrid 4-anilinoquinoline triazines have been synthesized and evaluated in vitro for their antimalarial activity against CQ-sensitive 3D7 strain of P. falciparum as well as for their cytotoxicity toward VERO cell line. Five compounds (19, 20, 23, 41 and 45) exhibited the antimalarial potency superior to CQ. Compounds 14 and 16 were found to be orally active at a dose of 100 mg/kg × 4 days against CQ-resistant strain of P. yoelii. Inhibition of β-hematin formation assay and molecular docking study has been conducted in order to gain insight into the mechanism of action of proposed targets for the 4-anilinoquinoline and triazine moiety of the hybrid compounds.     

Proteinase inhibitors as antileishmanial agents

Leishmania mexicana mexicana amastigote proteinase activity was largely inhibited by low concentrations of leupeptin, antipain and two epoxysuccinates, compounds known to affect cysteine proteinases. Of these inhibitors, only two had leishmanicidal activity. trans-Dicyclohexylepoxysuccinate at 10 μg/ ml inhibited the in vitro transformation of L. m. mexicana amastigotes to promastigotes by greater than 50%. Antipain was a potent antileishmanial agent, which inhibited promastigote growth over seven days by 50% at 0·5 μg/ml. The number of amastigotes that transformed in vitro to promastigotes was reduced 78% by antipain at 0·1 μg/ml. Each of the three diamidines investigated (pentamidine isothionate, amicarbilide and M and B 4596) exhibited marked antileishmanial activity, but only M and B 4596 had any significant effect (36% inhibition at 33 μg/ml) on L. m. mexicana amastigote proteinase activity.     

Benzo[b]acronycine derivatives: a novel class of antitumor agents

A hypothesis of bioactivation of the antitumor alkaloid acronycine by transformation of the 1,2-double bond into the corresponding epoxide in vivo and the suggestion that acronycine could interact with DNA, led to develop 1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine diesters (1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one diesters) as new anticancer drug candidates. Compared to acronycine these compounds were markedly more potent, both in terms of cytotoxicity and antitumor activity. The biological activity of these compounds was strongly related with their ability to give covalent adducts with purified as well as genomic DNA. Formation of those adducts involves alkylation of the exocyclic N-2 amino groups of guanines exposed in the minor groove of double helical DNA by the carbocation produced by the elimination of the acyloxy leaving group at position 1 of the drug. A transesterification process of the ester group from position 2 to position 1 accounted for the intense activity of cis-1-hydroxy-2-acyloxy-1,2-dihydrobenzo[b]acronycine derivatives. Cis-1,2-diacetoxy-1,2-dihydrobenzo[b]acronycine, which displays a particularly impressive broad antitumor spectrum, is currently developed by Servier Laboratories under the code S23906-1.     

Chemotherapy of leishmaniasis part III: synthesis and bioevaluation of novel aryl substituted terpenyl pyrimidines as antileishmanial agents

Some aryl substituted terpenyl pyrimidines 4 (a-p) have been synthesized using novel synthetic methods. The compounds were screened for in vitro antileishmanial activity against promastigotes. Compounds 4c, 4i and 4l showed IC(50) values as 35, 35 and 25 microg ml(-1).     

Synthesis and evaluation of new difluoromethyl azoles as antileishmanial agents

Several compounds of great pharmacological interest contain the triazole and imidazole rings. In order to find new drugs with antileishmanial activity we have synthesized and evaluated new imidazole and triazole compounds carrying either the carbaldehyde or the difluoromethylene functionalities against promastigote forms of Leishmania amazonensis. Among the compounds tested difluoromethylene azoles 4b and 8f have inhibited the parasite growth significantly. Our results show that the introduction of the difluoromethylene moieties has turned the inactive carbaldehydes into active antileishmanial compounds.     

The thiazolidinediones: a new class of antidiabetic agents

Insulin resistance is a fundamental feature of type 2 diabetes and is strongly associated with metabolic disorders which predict increased cardiovascular risk, including hypertension and dyslipidaemia. A new class of insulin-sensitizing agents, the thiazolidinediones, reduce insulin resistance and improve glycaemia both as monotherapy and in combination with sulphonylureas or metformin.     

2,3-Disubstituted 8-arylamino-3H-imidazo[4,5-g]quinazolines: a novel class of antitumor agents

A series of 2,3-disubstituted 8-arylamino-3H-imidazo[4,5-g]quinazolines were synthesized and evaluated for their cytotoxic activity in vitro against five human cancer cell lines (human lung carcinoma cell line: A549, human leukemia cell lines: K562 and Molt-4, human prostate cancer cell line: PC-3, human breast carcinoma cell line: MDA-MB-231). Most of these compounds show potent activity against these tumor cell lines, especially against the A549 cell line. The cell cycle analysis was also studied by flow cytometry measurement on A549 cell line.     

Synthesis and antileishmanial profile of some novel terpenyl pyrimidines

Some novel terpenyl pyrimidine derivatives 2(a-d) and 6(a-b) have been synthesised from alpha/beta-ionone keteneacetals 1 and 5. The terpenyl pyrimidine 2e has been synthesised from beta-ionone 3 in two steps in quantitative yield. The pyrimidine derivatives were screened for in-vivo antilesihmanial activity. The compounds 2d, 2e, 6a and 6b showed promising in-vivo antileishmanial activity.     

Synthesis and evaluation of new furanyl and thiophenyl azoles as antileishmanial agents

A series of benzyloxy furanyl and benzyloxy thiophenyl azoles were synthesized and screened for their in vitro antileishmanial activity against Leishmania donovani. Among all, 16 compounds have shown more than 90% inhibition against promastigotes at 20 μM while 11 compounds exhibited IC₅₀ in the range of 3.04-9.39 μM against amastigotes. Compound 4, a 3-chlorobenzyloxy furanyl imidazole emerged as the most active compound in the series with IC₅₀ value of 3.04 μM and SI value of 19.80, and was several folds more potent than the reference drugs miltefosine and miconazole.     

Chemotherapy of leishmaniasis part II: synthesis and bioevaluation of substituted arylketene dithioacetals as antileishmanial agents

Some novel aryl substituted ketene dithioacetals have been synthesized using novel synthetic methods. The compounds were screened against Leishmania donovani in hamsters for their activity profile. Some of the compounds inhibited 50-65% parasite growth at 50 mg kg(-1) x 5 days.     

Synthesis and biological evaluation of 4-nitro-substituted 1,3-diaryltriazenes as a novel class of potent antitumor agents

We describe the synthesis and biological activity of a new class of 1,3-diaryltriazenes, namely 4-nitro-substituted 1,3-diaryltriazenes. Structure-activity relationship analysis reveals that 1,3-diaryltriazenes can be modified from inactive to highly cytotoxic compounds by the introduction of two nitro groups at the para positions of benzene rings and two additional electron-withdrawing groups (bromo, chloro, trifluoromethyl or fluoro substituents) at their ortho position. In order to increase the solubility of the modified compounds, we introduced various acyl groups to their triazene nitrogen. The results of LC-MS/MS analysis showed that N-acyltriazenes can be considered as prodrugs of non-acylated triazenes. Selected 3-acetyl-1,3-bis(2-chloro-4-nitrophenyl)-1-triazene (8b) is highly cytotoxic against different tumor cell lines, including cisplatin-resistant laryngeal carcinoma cells. Notably, its antiproliferative activity is significantly higher against tumor cells than against normal cells. DNA binding analysis suggests that neither 8b nor its non-acylated derivative 8a bind into the minor groove of DNA. Instead, 8b induces reactive oxygen species that could provoke endoplasmic reticulum (ER^a) stress finally leading to apoptosis. Our data suggest that 4-nitro-substituted 1,3-diaryltriazenes are a new class of anticancer molecules which preferentially target malignant cells and may serve as potential antitumor agents.     

Ring-substituted imidazoles as a new class of anti-tuberculosis agents

We describe in vitro anti-Mycobacterium tuberculosis activities of ring-substituted-1H-imidazole-4-carboxylic acid derivatives (1-6), and 3-(2-alkyl-1H-imidazol-4-yl)-propionic acid derivatives (7-13) against drug-sensitive and drug-resistant M. tuberculosis H37Rv strains. The most effective analogues, 2f (R=R(1)=c-C(5)H(9)), and 2h (R=R(1)=c-C(6)H(11)) have produced >90% inhibition at a concentration of <6.25 microg/ml in the drug-sensitive screen. Upon further evaluation against drug-resistant strains, both analogues 2f and 2h produced an MIC value of 25.0 microg/ml. The observation of significant anti-tuberculosis activity in some of these analogues describes the discovery of novel ring-substituted-1H-imidazole-4-carboxylic acid ethyl esters as a new class of anti-tuberculosis agents.     

2,4-Disubstituted thiazoles II. A novel class of antitumor agents, synthesis and biological evaluation

A series of 2,4-disubstituted thiazole derivatives bearing N-n-butyl or N-cyclohexylthioureido synthon at position 2 and N-substituted thiosemicarbazone moiety at position 4 have been synthesized and tested for antitumor activity using the National Cancer Institute's in-vitro-disease-oriented antitumor screen. All of the tested compounds showed antineoplastic activity at concentrations less than 100 μM. Compounds 7, 9, 15 and 17 in particular showed activity with GI₅₀ (mean-graph midpoint) of 17.8, 8.5, 9.5 and 7.4 μM, respectively. The detailed syntheses, spectroscopic and biological data are discussed.     

Pyrimido[4,5-c]quinolin-1(2H)-ones as a novel class of antimitotic agents: Synthesis and in vitro cytotoxic activity

Several 2-amino-pyrimido[4,5-c]quinolin-1(2H)-ones variously substituted at positions 3, 5, and 9 were prepared from their corresponding lactones. The target compounds were investigated for in vitro cytotoxic activity against a panel of human cancer cell lines, namely, lung fibrosarcoma HT-1080, colon adenocarcinoma HT-29, and breast carcinoma MDA-MB-231. Analysis of data revealed that the presence of chloro at position 9 has a major positive impact on cytotoxic activity. Additional halogen substitution at the para position of the 3-phenyl group further enhances activity. Furthermore, compound (25) was found to dose-dependently inhibit tubulin polymerization. In accordance, flow cytometric analysis of the most potent compounds (23-26) indicated that the tested compounds induce cell cycle arrest in the G(2)/M phase. The obtained results introduce the rarely described pyrimido[4,5-c]quinolin-1(2H)-one ring system as a new scaffold for promising antimitotic agents.     

Multilevel latent class casemix modelling: a novel approach to accommodate patient casemix

Background  

Using routinely collected patient data we explore the utility of multilevel latent class (MLLC) models to adjust for patient casemix and rank Trust performance. We contrast this with ranks derived from Trust standardised mortality ratios (SMRs).