Evaluation of 7-arylaminopyrazolo[1,5-a]pyrimidines as anti-Plasmodium falciparum, antimalarial, and Pf-dihydroorotate dehydrogenase inhibitors.

Malaria remains one of the most serious global infectious diseases. An important target for antimalarial chemotherapy is the enzyme dihydroorotate dehydrogenase from Plasmodium falciparum (PfDHODH), which is responsible for the conversion of dihydroorotate to orotate in the de novo pyrimidine biosynthetic pathway. In this study, we have designed and synthesized fifteen 7-arylpyrazolo[1,5-a]pyrimidine derivatives using ring bioisosteric replacement and molecular hybridization of functional groups based on the highly active 5-methyl-N-(naphthalen-2-yl)-2-(trifluoromethyl)- [1,2,4]triazolo[1,5-a]pyrimidin-7-amine.

Synthesis, biological evaluation, and structure-activity relationship of clonazepam, meclonazepam, and 1,4-benzodiazepine compounds with schistosomicidal activity.

The inherent morbidity and mortality caused by schistosomiasis is a serious public health problem in developing countries. Praziquantel is the only drug in therapeutic use, leading to a permanent risk of parasite resistance. In search for new schistosomicidal drugs, meclonazepam, the 3-methyl-derivative of clonazepam, is still considered an interesting lead-candidate because it has a proven schistosomicidal effect in humans but adverse effects on the central nervous system did not allow its clinical use.

Molecular modeling and UV-vis spectroscopic studies on the mechanism of action of reversed chloroquine (RCQ).

Reversed chloroquine (RCQ) is a multiple ligand compound active against chloroquine-sensitive and resistant falciparum malaria. It is composed by a 4-aminoquinoline moiety (like that present in chloroquine (CQ)) joined to imipramine (IMP), a modulating agent that also showed intrinsic antiplasmodial activity against Brazilian Plasmodium falciparum isolates resistant to CQ. Molecular modeling and ultraviolet-visible spectroscopy (UV-vis) studies strongly suggest that the interaction between RCQ and heme is predominant through the quinoline moiety in a mechanism of action similar to that observed for CQ.

Cruzain inhibition by hydroxymethylnitrofurazone and nitrofurazone: investigation of a new target in Trypanosoma cruzi.

Nitrofurazone (NF) and its derivative, hydroxymethylnitrofurazone (NFOH), have presented antichagasic activity. NFOH has higher activity and lower mutagenicity. The aim of this work was to assess whether NF and its derivative NFOH would also be inhibitors of cruzain, besides their trypanothione reductase inhibitory activity.

The effects of 3-methylclonazepam on Schistosoma mansoni musculature are not mediated by benzodiazepine receptors.

Schistosomiasis is one of the most prevalent infectious diseases worldwide and classified as a neglected disease for which there is an urgent need for searching new drug candidates. According to TDR/WHO, existing leads with proven schistosomicidal activity, like meclonazepam, might be the objects of further exploration. Here, we decided to investigate if the benzodiazepine binding sites that we recently characterized in adult Schistosoma mansoni could represent the molecular target of meclonazepam for its effect on worm motility and morphological appearance.

Study of the interaction between hydroxymethylnitrofurazone and 2-hydroxypropyl-beta-cyclodextrin.

Chagas disease is a serious health problem in Latin America. Hidroxymethylnitrofurazone (NFOH) is a nitrofurazone prodrug more active than nitrofurazone against Trypanosoma cruzi. However, NFOH presents low aqueous solubility, high photodecomposition and high toxicity.

Topliss method in the optimization of salicylic Acid derivatives as potential antimycobacterial agents.

The Topliss method was used to guide a synthetic path in support of drug discovery efforts toward the identification of potent antimycobacterial agents. Salicylic acid and its derivatives, p-chloro, p-methoxy, and m-chlorosalicylic acid, exemplify a series of synthetic compounds whose minimum inhibitory concentrations for a strain of Mycobacterium were determined and compared to those of the reference drug, p-aminosalicylic acid. Several physicochemical descriptors (including Hammett's sigma constant, ionization constant, dipole moment, Hansch constant, calculated partition coefficient, Sterimol-L and -B4 and molecular volume) were considered to elucidate structure-activity relationships.

Hydroxymethylnitrofurazone:dimethyl-beta-cyclodextrin inclusion complex: a physical-chemistry characterization.

Hydroxymethylnitrofurazone (NFOH) is active against Trypanosoma cruzi; however, its low solubility and high toxicity precludes its current use in treatment of parasitosis. Cyclodextrin can be used as a drug carrier system, as it is able to form inclusion (host-guest) complexes with a wide variety of organic (guest) molecules. Several reports have shown the interesting use of modified beta-cyclodextrins in pharmaceutical formulation, to improve the bioavailability of drugs and to decrease their toxicity.

In vitro evaluation of verapamil and other modulating agents in Brazilian chloroquine-resistant Plasmodium falciparum isolates.

Verapamil, was assayed to record its modulating effect upon Brazilian Plasmodium falciparum isolates resistant to chloroquine. Other cardiovascular drugs known to be modulating agents in resistant malaria and/or multidrug-resistant neoplasias, including nifedipine, nitrendipine, diltiazem and propranolol, were also evaluated. Concentrations similar to those for cardiovascular therapy were used in the in vitro microtechnique for antimalarial drug susceptibility.

In vitro chloroquine resistance modulation study on fresh isolates of Brazilian Plasmodium falciparum: intrinsic antimalarial activity of phenothiazine drugs.

Phenothiazine drugs - fluphenazine, chlorpromazine, methotrimeprazine and trifluoperazine - were evaluated as modulating agents against Brazilian chloroquine-resistant fresh isolates of Plasmodium falciparum. Aiming to simulate therapeutic schedules, chloroquine was employed at the concentration used for sensitive falciparum malaria treatment and anti-psychotic therapeutic concentrations of the phenothiazine drugs were adopted in two-fold serial dilutions. The in vitro microtechnique for drug susceptibility was employed.