Evaluation of the Anti-Leishmania mexicana and -Trypanosoma brucei Activity and Mode of Action of 4,4'-(Arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol).

Trypanosomiasis and leishmaniasis are neglected infections caused by trypanosomatid parasites. The first-line treatments have many adverse effects, high costs, and are prone to resistance development, hence the necessity for new chemotherapeutic options. In line with this, twenty five 4,4'-(arylmethylene)bis(1H-pyrazol-5-ols) derivatives were synthesized and evaluated in vitro for their anti-trypanosomatid activity. Ten and five compounds from this series showed IC50 ≤ 10 µM against the promastigote and the bloodstream stage of Leishmania mexicana and Trypanosoma brucei brucei, respectively. Overall, derivatives with pyrazole rings substituted with electron-withdrawing groups proved more active than those with electron-donating groups. The hits proved moderately selective towards L. mexicana and T. brucei (selectivity index, SI, compared to murine macrophages = 5−26). The exception was one derivative displaying an SI (>111−189) against T. brucei that surpassed, by >6-fold, the selectivity of the clinical drug nifurtimox (SI = 13−28.5). Despite sharing a common scaffold, the hits differed in their mechanism of action, with halogenated derivatives inducing a rapid and marked intracellular oxidative milieu in infective T. brucei. Notably, most of the hits presented better absorption, distribution, metabolism, and excretion (ADME) properties than the reference drugs. Several of the bioactive molecules herein identified represent a promising starting point for further improvement of their trypanosomatid potency and selectivity.

Synthesis and Evaluation of Biological Activities of Bis(spiropyrazolone)cyclopropanes: A Potential Application against Leishmaniasis.

This work focuses on the search and development of drugs that may become new alternatives to the commercial drugs currently available for treatment of leishmaniasis. We have designed and synthesized 12 derivatives of bis(spiropyrazolone)cyclopropanes. We then characterized their potential application in therapeutic use. For this, the in vitro biological activities against three eukaryotic models-S. cerevisiae, five cancer cell lines, and the parasite L. mexicana-were evaluated. In addition, cytotoxicity against non-cancerous mammalian cells has been evaluated and other properties of interest have been characterized, such as genotoxicity, antioxidant properties and, in silico predictive adsorption, distribution, metabolism, and excretion (ADME). The results that we present here represent a first screening, indicating two derivatives of bis(spiropyrazolone)cyclopropanes as good candidates for the treatment of leishmaniasis. They have good specificity against parasites with respect to mammalian cells.

Characterization of Antimicrobial, Antioxidant, and Leishmanicidal Activities of Schiff Base Derivatives of 4-Aminoantipyrine.

Our main interest is the characterization of compounds to support the development of alternatives to currently marketed drugs that are losing effectiveness due to the development of resistance. Schiff bases are promising biologically interesting compounds having a wide range of pharmaceutical properties, including anti-inflammatory, antipyretic, and antimicrobial activities, among others. In this work, we have synthesized 12 Schiff base derivatives of 4-aminoantipyrine. In vitro antimicrobial, antioxidant, and cytotoxicity properties are analyzed, as well as in silico predictive adsorption, distribution, metabolism, and excretion (ADME) and bioactivity scores. Results identify two potential Schiff bases: one effective against E. faecalis and the other with antioxidant activity. Both have reasonable ADME scores and provides a scaffold for developing more effective compounds in the future. Initial studies are usually limited to laboratory in vitro approaches, and following these initial studies, much research is needed before a drug can reach the clinic. Nevertheless, these laboratory approaches are mandatory and constitute a first filter to discriminate among potential drug candidates and chemical compounds that should be discarded.

Different role of cAMP pathway on the human mast cells HMC-1(560) and HMC-1(560,816) activation.

HMC-1 are inflammatory cells that release vasoactive substances such as histamine. These cells have the c-kit receptor permanently activated in the membrane due to mutations in the proto-oncogene c-kit: Val-560 → Gly and Asp-816 → Val. Thus, there are two known cellular lines: HMC-1(560) and HMC-1(560,816) . These mutations are involved in a disease called mastocitosys. In the present paper both lines were used to study the influence of cAMP/PKA/PDEs pathway on the histamine release and Ca(2+) signaling since this pathway is often involved in these process. For this, the cells were preincubated with cAMP/PKA/PDEs modulators such as dibutyryl cAMP (dbcAMP), forskolin, H89, rolipram, IBMX, or imidazole and then stimulated with ionomycin. When cells were stimulated with agents that increase cAMP levels, the histamine release was not modified in HMC-1(560) but decreased in HMC-1(560,816) cells. The same happened when PKA was blocked. Furthermore, PDEs role on histamine release was independent of cAMP in HMC-1(560) cells and possibly also in HMC-1(560,816) cells. By contrast, the modulation of PKA and PDEs together changed the response in both cellular lines, therefore a relationship between them was suggested. All these modulatory effects on histamine release are Ca(2+) -independent. On the other hand, the effect of c-kit modulation on the cAMP/PKA/PDEs pathway was also checked. This receptor was blocked with STI571 (imatinib) and BMS-354825 (dasatinib), but only the last one caused a decrease in the cellular response to ionomycin. This article demonstrates for the first time than the cAMP/PKA/PDEs pathway is involved in the activation of HMC-1(560) and HMC-1(560,816) cells.