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1.
Dalton Trans ; 47(21): 7245-7255, 2018 May 29.
Article in English | MEDLINE | ID: mdl-29757339

ABSTRACT

Reaction of benzohydroxamic acid (Bha), 2-pyridinehydroxamic acid (2-pyha), 2-amino-phenylhydroxamic acid (2-NH2-pha) and salicylhydroxamic acid (Sha) with SbCl3 in ethanol gave the corresponding novel hydroxamato Sb(iii) complexes, [Sb(Bha-1H)2Cl] 1, [SbCl2(2-pyha-1H)] 2, [Sb(2-NH2-pha-1H)(2-NH3-pha-1H)]Cl23 and [SbCl(Sha-1H)2] 4. In all cases the hydroxamic acids coordinate to the Sb centres in the typical bidentate hydroxamato (O,O') coordination mode, via the carbonyl oxygen and deprotonated hydroxyl group. Reaction of the histone deacetylase inhibitor (HDACi) suberoylanilidehydroxamic acid (SAHA) with Sb(OEt)3 gave the Sb(iii) hydroxamato/hydroximato complex, [Sb(SAHA-1H)(SAHA-2H)] 6. All test complexes significantly inhibited the promastigote proliferation of Leishmania amazonensis and L. chagasi and induced substantial changes in the general morphology of the parasites, including reduction in size and loss of flagellum, when compared to the untreated promastigotes. A dose-response approach using the test complexes showed a decreased in plasma membrane permeability and the mitochondrial dehydrogenase activities of the Leishmania species. [Sb(Bha-1H)2Cl] exhibited the best activity and was superior to the Sb HDACi complex 6. Though 1 exhibited noteworthy anti-leishmanial activity, the selectivity indexes determined suggest that [Sb(2-NH2-pha-1H)(2-NH3-pha-1H)]Cl23 is the test complex that merits further investigation as a potential anti-leishmanial agent.


Subject(s)
Antimony/pharmacology , Antiprotozoal Agents/pharmacology , Hydroxamic Acids/pharmacology , Leishmania/drug effects , Antimony/chemistry , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/chemistry , Cell Survival/drug effects , Crystallography, X-Ray , Hydroxamic Acids/chemistry , Leishmania/cytology , Models, Molecular , Molecular Structure , Parasitic Sensitivity Tests
2.
Curr Med Chem ; 22(18): 2225-35, 2015.
Article in English | MEDLINE | ID: mdl-25994861

ABSTRACT

Chagas' disease is one of the most impactful and prevalent neglected tropical diseases in the Americas, specially affecting the poor and underdeveloped areas in Latin America. Aggravating this scenario, the medicines used in the current chemotherapy are old, toxic and present a low efficacy to treat the chronic stage of this disease. In addition, resistant strains of Trypanosoma cruzi, the etiological agent, are frequently reported. So, there is an imperative requirement for novel chemotherapeutic options to treat this debilitating disease. In this context, peptidases have emerged as potential targets and, consequently, proteolytic inhibitors have confirmed to be valuable drugs against several human pathologies. In this line of thinking, T. cruzi produces a major multifunctional cysteine peptidase, named cruzipain, which directly and/or indirectly orchestrates several physiological and pathological processes, which culminate in a successful parasitic infection. Taken together, these findings point out that cruzipain is one of the most important targets for driving a chemotherapy approach against the human pathogen T. cruzi. The present review summarizes some of the recent advances and failures in this area, with particular emphasis on recently published studies.


Subject(s)
Antineoplastic Agents/pharmacology , Antiprotozoal Agents/pharmacology , Cysteine Endopeptidases/pharmacology , Trypanosoma cruzi/drug effects , Antineoplastic Agents/chemistry , Antiprotozoal Agents/chemistry , Cysteine Endopeptidases/chemistry , Molecular Conformation , Parasitic Sensitivity Tests , Protozoan Proteins
3.
Curr Med Chem ; 20(25): 3174-85, 2013.
Article in English | MEDLINE | ID: mdl-23899207

ABSTRACT

The treatment for both leishmaniasis and trypanosomiasis, which are severe human infections caused by trypanosomatids belonging to Leishmania and Trypanosoma genera, respectively, is extremely limited because of concerns of toxicity and efficacy with the available anti-protozoan drugs, as well as the emergence of drug resistance. Consequently, the urgency for the discovery of new trypanosomatid targets and novel bioactive compounds is particularly necessary. In this context, the investigation of changes in parasite gene expression between drug resistant/sensitive strains and in the up-regulation of virulence-related genes in infective forms has brought to the fore the involvement of calpain-like proteins in several crucial pathophysiological processes performed by trypanosomatids. These studies were encouraged by the publication of the complete genome sequences of three human pathogenic trypanosomatids, Trypanosoma brucei, Trypanosoma cruzi and Leishmania major, which allowed in silico analyses that in turn directed the identification of numerous genes with interesting chemotherapeutic characteristics, including a large family of calpain-related proteins, in which to date 23 genes were assigned as calpains in T. brucei, 40 in T. cruzi and 33 in L. braziliensis. In the present review, we intend to add to these biochemical/biological reports the investigations performed upon the inhibitory capability of calpain inhibitors against human pathogenic trypanosomatids.


Subject(s)
Calpain/antagonists & inhibitors , Protease Inhibitors/therapeutic use , Protozoan Proteins/antagonists & inhibitors , Trypanosomiasis/drug therapy , Calpain/metabolism , Humans , Peptides/chemistry , Peptides/pharmacology , Peptides/therapeutic use , Protease Inhibitors/pharmacology , Protozoan Proteins/metabolism , Trypanosoma/drug effects , Trypanosoma/enzymology , Trypanosomiasis/parasitology
4.
Curr Med Chem ; 19(17): 2715-37, 2012.
Article in English | MEDLINE | ID: mdl-22455582

ABSTRACT

Infections caused by resistant microorganisms often fail to respond to conventional therapy, resulting in prolonged illness, increased treatment costs and greater risk of death. Consequently, the development of novel antimicrobial drugs is becoming more demanding every day since the existing drugs either have too many side-effects or they tend to lose effectiveness due to the selection of resistant strains. In view of these facts, a number of new strategies to obstruct vital biological processes of a microbial cell have emerged; one of these is focused on the use of metal-chelating agents, which are able to selectively disturb the essential metal metabolism of the microorganism by interfering with metal acquisition and bioavailability for crucial reactions. The chelation activity is able to inhibit the biological role of metal-dependent proteins (e.g., metalloproteases and transcription factors), disturbing the microbial cell homeostasis and culminating in the blockage of microbial nutrition, growth and development, cellular differentiation, adhesion to biotic (e.g., extracellular matrix components, cell and/or tissue) and abiotic (e.g., plastic, silicone and acrylic) structures as well as controlling the in vivo infection progression. Interestingly, chelating agents also potentiate the activity of classical antimicrobial compounds. The differences between the microorganism and host in terms of the behavior displayed in the presence of chelating agents could provide exploitable targets for the development of an effective chemotherapy for these diseases. Consequently, metal chelators represent a novel group of antimicrobial agents with potential therapeutic applications. This review will focus on the anti-fungal and anti-protozoan action of the most common chelating agents, deciphering and discussing their mode of action.


Subject(s)
Anti-Infective Agents/pharmacology , Antiprotozoal Agents/pharmacology , Chelating Agents/pharmacology , Fungi/drug effects , Animals , Fungi/growth & development , Fungi/pathogenicity , Humans , Plasmodium/drug effects , Plasmodium/growth & development , Plasmodium/pathogenicity , Trypanosoma/drug effects , Trypanosoma/growth & development , Trypanosoma/pathogenicity
5.
Parasitology ; 136(4): 433-41, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19250597

ABSTRACT

In this paper, we aimed to explore the effects of the calpain inhibitor III (MDL28170) and to detect calpain-like molecules (CALPs) in epimastigote forms of Trypanosoma cruzi isolate Dm28c. MDL28170 at 70 microM promoted a powerful reduction in the growth rate after 48 h. The IC50 value was calculated to be 31.7 microM. This inhibitor promoted an increase in the cellular volume, but not cell lysis, resulting in a trypanostatic effect. T. cruzi CALPs presented a strong cross-reactivity with anti-Drosophila melanogaster calpain and anti-cytoskeleton-associated protein from Trypanosoma brucei antibodies, and labelling was found mainly intracellularly. Furthermore, an 80 kDa reactive protein was detected by Western blotting assays. No significant cross-reactivity was found with anti-human brain calpain antibody. The expression of CALPs was decreased in cells kept for long periods in axenic cultures in comparison to a strain recently isolated from mice, as well as in MDL28170-treated cells, the latter being paralleled by an increased expression of cruzipain. Different levels of CALPs expression were also detected in distinct phylogenetic lineages, like Y strain (lineage TcII), Dm28c (lineage TcI) [corrected] and INPA6147 strain (Z3 zymodeme). These results may contribute for the investigation of the functions of CALPs in trypanosomatids.


Subject(s)
Calpain/metabolism , Cysteine Proteinase Inhibitors/pharmacology , Dipeptides/pharmacology , Protozoan Proteins/metabolism , Trypanosoma cruzi , Animals , Antibodies, Protozoan/immunology , Calpain/chemistry , Calpain/genetics , Calpain/immunology , Gene Expression Regulation , Humans , Mice , Protozoan Proteins/chemistry , Protozoan Proteins/genetics , Protozoan Proteins/immunology , Trypanosoma cruzi/drug effects , Trypanosoma cruzi/enzymology , Trypanosoma cruzi/growth & development , Trypanosoma cruzi/immunology
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