In vivo and in vitro anti-leishmanial activities of 4-nitro-N-pyrimidin- and N-pyrazin-2-ylbenzenesulfonamides, and N2-(4-nitrophenyl)-N1-propylglycinamide

Dea-Ayuela, María Auxiliadora; Castillo, Encarna; González‐Álvarez, Marta; Vega, Celeste; Rolón, Míriam; Bolás‐Fernández, F.; Borrás, Joaquı́n; González‐Rosende, M. Eugenia

doi:10.1016/j.bmc.2009.09.030

Cited by 39 publications

(49 citation statements)

References 36 publications

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“…Amastigotes of L. infantum (MCAN/ES/92/BCN83) were harvested from spleens of infected hamsters and then cultured in NNN medium containing penicillin (200 IU) and streptomycin (2 mg/ml) for 2 days, until transformation into promastigotes. Promastigotes were grown for 7 days, as described elsewhere [18], and were then harvested, washed and resuspended for counting. The animals were anaesthetized with sodium pentobarbital and then infected with 10 7 promastigotes per animal, administered via the intracardiac route.…”

Section: Methodsmentioning

confidence: 99%

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Synthetic Oxoisoaporphine Alkaloids: In Vitro, In Vivo and In Silico Assessment of Antileishmanial Activities

et al. 2013

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Leishmaniasis is a growing health problem worldwide. As there are certain drawbacks with the drugs currently used to treat human leishmaniasis and resistance to these drugs is emerging, there is a need to develop novel antileishmanial compounds, among which isoquinoline alkaloids are promising candidates. In this study, 18 novel oxoisoaporphine derivatives were synthesized and their possible antileishmanial activity was evaluated. The in vitro activity of these derivatives against Leishmania amazonensis axenic amastigotes was first evaluated, and the selected compounds were then tested in an inhibition assay with promastigotes of L. infantum, L. braziliensis, L. amazonensis and L. guyanensis, and with intracellular amastigotes of L. infantum and L. amazonensis. Finally, the most active compounds, OXO 1 (2,3-dihydro-7H-dibenzo[de,h]quinolin-7-one) and OXO 13 (2,3,8,9,10,11-hexahydro-7H-dibenzo[de,h]quinolin-7-one), were tested in BALB/c mice infected with L. infantum. Treatment of mice at a dose of 10 mg/kg with OXO 1 yielded significant reductions (p<0.05) in parasite burden in liver and spleen (99% and 78%, respectively) whereas with OXO 13 were not significant. Although previous reports suggest that this family of molecules displays inhibitory activity against monoamine oxidase A and acetylcholinesterase, these enzymes were not confirmed as targets for antileishmanial activity on the basis of the present results. However, after development of a new bioinformatics model to analyze the Leishmania proteome, we were able to identify other putative targets for these molecules. The most promising candidates were four proteins: two putative pteridine reductase 2 (1MXF and 1MXH), one N-myristoyltransferase (2WUU) and one type I topoisomerase (2B9S).

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Section: Methodsmentioning

confidence: 99%

“…After eliminating cell debris, the suspension was centrifuged, the supernatants were discarded and the pellets were resuspended as previously described [18]. Aliquots (200 µl) of the suspension were transferred to each well of 96-well microtiter plates containing NNN medium supplemented with antibiotics.…”

Section: Methodsmentioning

confidence: 99%

Synthetic Oxoisoaporphine Alkaloids: In Vitro, In Vivo and In Silico Assessment of Antileishmanial Activities

et al. 2013

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“…The sulfonamide 2e was easily obtained by the reaction of 5-aminoisoquinoline with phenylsulfonyl chloride in pyridine at room temperature according to the literature (Scheme 4) [33,34]. …”

Section: Resultsmentioning

confidence: 99%

Seeking for Non-Zinc-Binding MMP-2 Inhibitors: Synthesis, Biological Evaluation and Molecular Modelling Studies

Ammazzalorso

Filippis

Campestre

et al. 2016

IJMS

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Matrix metalloproteinases (MMPs) are an important family of zinc-containing enzymes with a central role in many physiological and pathological processes. Although several MMP inhibitors have been synthesized over the years, none reached the market because of off-target effects, due to the presence of a zinc binding group in the inhibitor structure. To overcome this problem non-zinc-binding inhibitors (NZIs) have been recently designed. In a previous article, a virtual screening campaign identified some hydroxynaphtyridine and hydroxyquinoline as MMP-2 non-zinc-binding inhibitors. In the present work, simplified analogues of previously-identified hits have been synthesized and tested in enzyme inhibition assays. Docking and molecular dynamics studies were carried out to rationalize the activity data.

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“…N-(1H-Indazol-5-yl)-4-nitrobenzenesulfonamide (5a) [17] H,4.38,N,8.69,S,9.94. Found: C,66.86,H,4.65,N,8.48,S,9.59.…”

Section: Synthesis and Characterizationmentioning

confidence: 99%

“…,3-dihydro-1H-inden-5-yl)-benzenesulfonamide(13a)[17].Yield: 91%, mp: 150-154 ºC, 1 H NMR (300 MHz, DMSO-d6 ) δ = 1.92(m, 2H), 2.72 (m, 4H), 6.84 (dd, J = 8.1, J = 2.1, 1H),6.94 (s, 1H), 7.02(d, J = 8.1, 1H), 7.53(m, 3H), 7.72(d, J = 7.9, 2H), 10.1 (brs, 1H, NH), 13 C NMR (75 MHz, DMSO-d6 ) δ: 25.4 (CH 2 ), 31.9 (CH 2 ), 32.6 (CH 2 ), 117.1 (CH), 118.9 (CH), 124.9 (CH), 127.0 (CH), 129.5 (CH), 134.0 (CH), 136.0 (C), 139.9 (C), 140.0 (C), 145.4 (C), HRMS-EI + : m/z calcd for C 15 H 15 NO 2 S: 273.0823, found: 273.0826. Anal.…”

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confidence: 99%

N-(2-methyl-indol-1H-5-yl)-1-naphthalenesulfonamide: A novel reversible antimitotic agent inhibiting cancer cell motility

Aceves-Luquero

Galiana‐Roselló

Ramis

et al. 2016

Biochemical Pharmacology

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A series of compounds containing the sulfonamide scaffold were synthesized and screened for their in vitro anticancer activity against a representative panel of human cancer cell lines, leading to the identification of N-(2-methyl-1H-indol-5-yl)-1-naphthalenesulfonamide (8e) as a compound showing a remarkable activity across the panel, with IC50 values in the nanomolar-to-low micromolar range. Cell cycle distribution analysis revealed that 8e promoted a severe G2/M arrest, which was followed by cellular senescence as indicated by the detection of senescence-associated β-galactosidase (SA-β-gal) in 8e-treated cells. Prolonged 8e treatment also led to the onset of apoptosis, in correlation with the detection of increased Caspase 3/7 activities. Despite increasing γ-H2A.X levels, a well-established readout for DNA double-strand breaks, in vitro DNA binding studies with 8e did not support interaction with DNA. In agreement with this, 8e failed to activate the cellular DNA damage checkpoint. Importantly, tubulin staining showed that 8e promoted a severe disorganization of microtubules and mitotic spindle formation was not detected in 8e-treated cells. Accordingly, 8e inhibited tubulin polymerization in vitro in a dose-dependent manner and was also able to robustly inhibit cancer cell motility. Docking analysis revealed a compatible interaction with the colchicine-binding site of tubulin. Remarkably, these cellular effects were reversible since disruption of treatment resulted in the reorganization of microtubules, cell cycle re-entry and loss of senescent markers. Collectively, our data suggest that this compound may be a promising new anticancer agent capable of both reducing cancer cell growth and motility.

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In vivo and in vitro anti-leishmanial activities of 4-nitro-N-pyrimidin- and N-pyrazin-2-ylbenzenesulfonamides, and N2-(4-nitrophenyl)-N1-propylglycinamide

Cited by 39 publications

References 36 publications

Synthetic Oxoisoaporphine Alkaloids: In Vitro, In Vivo and In Silico Assessment of Antileishmanial Activities

Synthetic Oxoisoaporphine Alkaloids: In Vitro, In Vivo and In Silico Assessment of Antileishmanial Activities

Seeking for Non-Zinc-Binding MMP-2 Inhibitors: Synthesis, Biological Evaluation and Molecular Modelling Studies

N-(2-methyl-indol-1H-5-yl)-1-naphthalenesulfonamide: A novel reversible antimitotic agent inhibiting cancer cell motility

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