- In vitro activity and mode of action of distamycin analogues against African trypanosomes
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Distamycin, a natural polyamide containing three heterocycle rings with a polar end, has inspired several groups to prepare synthetic analogues, which proved to have anti-trypanosomal and anti-tumoral activity. We describe the synthesis of bi and tri thiazoles amides that harbor different substitutions at their ends and the evaluation of their anti-Trypanosoma brucei activity. The most active compound 10b showed better biological activity (EC50310 nM and selectivity index 16) than the control drug nifurtimox (EC5015 μM and selectivity index 10). Studies on the mode of action show that the parasiticidal activity of 10b originates from disruption of lysosomal homeostasis, which is followed by release of redox active iron, an increase in oxidizing species and collapse of cell membrane integrity. In this respect, our study suggests that non-charged lipophylic distamycins destabilize cell membranes.
- Franco, Jaime,Medeiros, Andrea,Benítez, Diego,Perelmuter, Karen,Serra, Gloria,Comini, Marcelo A.,Scarone, Laura
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- New BI and TRI-Thiazole copper (II) complexes in the search of new cytotoxic drugs against breast cancer cells
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New thiazolyl derivatives (BT and TT) and their copper (II) complexes [Cu2Cl2(BT)2] (Cu-BT) and [Cu4ClO2(TT)2]PF6?3.5H2O (Cu-TT) were synthesized and characterized by elemental analysis, 1H NMR and 13C NMR, HRMS, X-ray diffraction, IR and UV–Vis spectroscopies. The crystal structure of Cu-BT shows the formation of a dinuclear complex where each copper(II) center is bonded to two thiazol N atoms, from different BT ligands, one deprotonated amide N atom, an O atom from the ester terminal groups and a chlorine atom. The structure found for Cu-TT is a positively charged tetranuclear moiety containing two deprotonated TT ligands, a chlorine anion, two hydroxide anions acting as bridges between the copper centers and a water molecule. The cytotoxic activity of both copper complexes was evaluated on metastatic breast cancer cell lines, characterized for its rapidly dividing behavior. Both, Cu-BT and Cu-TT, show higher cytotoxic activity against these tumor cells than free BT and TT and also than cisplatin. In addition, we found that both complexes interact with DNA. Consistently, they also show cytotoxicity against a rapidly dividing non-tumor cell line, although with higher IC50, being such interaction and selectivity an indicator of the possible coexistence of more than one mechanism of action.
- Alvarez, Natalia,Velluti, Francesca,Guidali, Florencia,Serra, Gloria,Gabriela Kramer,Ellena, Javier,Facchin, Gianella,Scarone, Laura,Torre, María H.
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- An efficient synthesis of 2,4′-bi-1,3-oxa(thia)zoles as scaffolds for bioactive products
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A rapid and efficient methodology to prepare 2,4′-bi-1,3-azoles as scaffolds for biologically active marine natural products is described. Hantzsch reaction and oxidative cyclodehydration of β-hydroxy amides or thioamides were used to construct the azole rings. The obtained biheterocycles displayed no cytotoxicity on HCT-15 cell line.
- Pena,Scarone,Manta,Serra
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experimental part
p. 703 - 709
(2012/02/01)
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- Thiazole[4,5-C]pyridine derivatives
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The invention relates to compounds of general formula I: wherein R1, R2 and R3 are as defined in the description such compounds are metabotropic glutamate receptor antagonists and are useful in the treatment or prevention of mGluR5 receptor mediated disorders.
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Page/Page column 10
(2008/06/13)
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- Thiazole-4-carboxyamide derivatives
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The present invention is concerned with novel thiazole 4-carboxyamide derivatives of the general formula (I) and with methods for the preparation thereof, which compounds are useful as metabotropic glutamate receptor antagonists: wherein R1 to R4 are as defined in the specification.
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Page/Page column 31
(2008/06/13)
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- 4(SPIROPIPERIDINYL)METHYL SUBSTITUTED PYRROLIDINES AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
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3-Substituted pyrrolidines having a spiropiperidinylmethyl substituent on the 4-position of the ring are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-3 and/or CCR-5.
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- 4-[(4-(CARBOXYETHYL) PIPERIDINYL) METHYL] PYRROLIDINES AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
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3-Substituted pyrrolidines having a 4-carboxypiperidinylmethyl substituent on the 4-position of the ring are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-3 and/or CCR-5.
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- HIV protease inhibitors
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The present invention discloses novel isoquinoline carboxamide derivatives which are HIV protease inhibitors or prodrugs thereof, a process for their manufacture, pharmaceutical compositions and the use of such compounds in medicine. In particular, the compounds are hydroxyethylamine tripeptide mimetics which act as inhibitors of the HIV aspartyl protease, an essential enzyme in the replicative life cycle of HIV. Consequently, the compounds of this invention may be advantageously used in the treatment of HIV infection, either alone or in combination with other inhibitors of HIV viral replication or with pharmacoenhancers such as cytochrome P450 inhibitors.
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