Phenotypic and Target-Directed Screening Yields New Acaricidal Alternatives for the Control of Ticks.

Rhipicephalus microplus, the "common cattle tick", is the most important ectoparasite in livestock worldwide due to the economic and health losses it produces. This tick is a vector for pathogens of several tick-borne diseases. In Latin American countries, damages reach approximately USD 500 million annually due to tick infections, as well as tick-borne diseases. Currently, resistant populations for every chemical group of acaricides have been reported, posing a serious problem for tick control. This study aims to find new alternatives for controlling resistant ticks with compounds derived from small synthetic organic molecules and natural origins. Using BME26 embryonic cells, we performed phenotypic screening of 44 natural extracts from 10 Mexican plants used in traditional medicine, and 33 compounds selected from our chemical collection. We found 10 extracts and 13 compounds that inhibited cell growth by 50% at 50 µg/mL and 100 µM, respectively; the dose-response profile of two of them was characterized, and these compounds were assayed in vitro against different life stages of Rhipicephalus microplus. We also performed a target-directed screening of the activity of triosephosphate isomerase, using 86 compounds selected from our chemical collection. In this collection, we found the most potent and selective inhibitor of tick triosephosphate isomerase reported until now. Two other compounds had a potent acaricidal effect in vitro using adults and larvae when compared with other acaricides such as ivermectin and Amitraz. Those compounds were also selective to the ticks compared with the cytotoxicity in mammalian cells like macrophages or bovine spermatozoids. They also had a good toxicological profile, resulting in promising acaricidal compounds for tick control in cattle raising.

Pyrazol(in)e derivatives of curcumin analogs as a new class of anti-Trypanosoma cruzi agents.

Aim: We report the synthesis and biological evaluation of a small library of 15 functionalized 3-styryl-2-pyrazolines and pyrazoles, derived from curcuminoids, as trypanosomicidal agents. Methods & results: The compounds were prepared via a cyclization reaction between the corresponding curcuminoids and the appropriate hydrazines. All of the derivatives synthesized were investigated for their trypanosomicidal activities. Compounds 4a and 4e showed significant activity against epimastigotes of Trypanosoma cruzi, with IC50 values of 5.0 and 4.2 µM, respectively, accompanied by no toxicity to noncancerous mammalian cells. Compound 6b was found to effectively inhibit T. cruzi triosephosphate isomerase. Conclusion: The up to 16-fold higher potency of these derivatives compared with their curcuminoid precursors makes them a promising new family of T. cruzi inhibitors.