Enzymatic Synthesis of Austroeupatol Esters with Enhanced Antiprotozoal Activity.

Austroeupatol, the principal diterpene isolated from the invasive shrub , holds promise for structural diversification and biological assessment of its derivatives due to its abundant availability and high yield isolation. We propose an efficient enzymatic synthesis of a series of austroeupatol esters derived from aliphatic and heterocyclic carboxylic acids. Systematic optimization of reaction parameters, including enzyme type and quantity, acylating agent amount, solvent, and temperature, was conducted.

Optimization of the 2-arylquinazoline-4(3)one scaffold for a selective and potent antitrypanosomal agent: modulation of the mechanism of action through chemical functionalization.

We sought to identify a potent and selective antitrypanosomal agent through modulation of the mechanism of action of a 2-arylquinazoline scaffold as an antitrypanosomal agent chemical functionalization at the 4-position. We wished to use the: (i) susceptibility of trypanosomatids towards nitric oxide (NO) and reactive oxygen species (ROS); (ii) capacity of the 4-substituted quinazoline system to act as an antifolate agent. Three quinazolin-based moieties that differed from each other by having at the 4-position key pharmacophores targeting the induction of NO and ROS production were evaluated against and parasites and their modes of action were explored.

Preclinical Studies and Drug Combination of Low-Cost Molecules for Chagas Disease.

Chagas disease is caused by the protozoan (). It remains the major parasitic disease in Latin America and is spreading worldwide, affecting over 10 million people. Hundreds of new compounds with trypanosomicidal action have been identified from different sources such as synthetic or natural molecules, but they have been deficient in several stages of drug development (toxicology, scaling-up, and pharmacokinetics).

Synthesis and Antitrypanosomal and Mechanistic Studies of a Series of 2-Arylquinazolin-4-hydrazines: A Hydrazine Moiety as a Selective, Safe, and Specific Pharmacophore to Design Antitrypanosomal Agents Targeting NO Release.

Nitric oxide (NO) represents a valuable target to design antitrypanosomal agents by its high toxicity against trypanosomatids and minimal side effects on host macrophages. The progress of NO-donors as antitrypanosomal has been restricted by the high toxicity of their agents, which usually is based on NO-heterocycles and metallic NO-complexes. Herein, we carried out the design of a new class of NO-donors based on the susceptibility of the hydrazine moiety connected to an electron-deficient ring to be reduced to the amine moiety with release of NO.

Preclinical Studies in Anti- Drug Development.

The trypanosomatid parasites , and are the causative agents of human African trypanosomiasis, Chagas Disease and Leishmaniasis, respectively. These infections primarily affect poor, rural communities in the developing world, and are responsible for trapping sufferers and their families in a disease/poverty cycle. The development of new chemotherapies is a priority given that existing drug treatments are problematic.

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

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. 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.

Antiprotozoal Compounds from (Asteraceae).

The dewaxed dichloromethane extract of and the compounds isolated from it were tested for their activity on epimastigotes and promastigotes. The extract of showed activity against both parasites with IC values of 7 g/mL and 31 g/mL, respectively. Fractionation of the dichloromethane extract led to the isolation of euparin, jaceidin, santhemoidin C, and eucannabinolide.

A Nature-Inspired Design Yields a New Class of Steroids Against Trypanosomatids.

Chagas disease and Leishmaniasis are neglected endemic protozoan diseases recognized as public health problems by the World Health Organization. These diseases affect millions of people around the world however, efficient and low-cost treatments are not available. Different steroid molecules with antimicrobial and antiparasitic activity were isolated from diverse organisms (ticks, plants, fungi).

Infrared-Based Motility Assay Identified New Hits for Nematicide Drug Development.

Nematode parasites have a profound impact on humankind, infecting nearly one-quarter of the world's population, as well as livestock. There is a pressing need for discovering nematicides due to the spread of resistance to currently used drugs. The free-living nematode is a formidable experimentally tractable model organism that offers key advantages in accelerating nematicide discovery.

Novel and Selective Triosephosphate Isomerase Inhibitors with Acaricidal Activity.

The cattle tick is one of the most important ectoparasites causing significant economic losses for the cattle industry. The major tool of control is reducing the number of ticks, applying acaricides in cattle. However, overuse has led to selection of resistant populations of to most of these products, some even to more than one active principle.

Polypharmacology in the Treatment of Chagas Disease.

The current treatment of Chagas disease is based on monopharmacology where the used drugs have limited efficacy and severe side effects. In order to overcome these limitations, some tools have been described including the development or isolation of new drugs, drug repositioning, and polypharmacology. Here, we review the polypharmacology strategy where compounds belonging to different structural chemotypes were combined in order to affect different biochemical pathways of T.

Looking for combination of benznidazole and Trypanosoma cruzi-triosephosphate isomerase inhibitors for Chagas disease treatment.

Background: The current chemotherapy for Chagas disease is based on monopharmacology with low efficacy and drug tolerance. Polypharmacology is one of the strategies to overcome these limitations.

Objectives: Study the anti-Trypanosoma cruzi activity of associations of benznidazole (Bnz) with three new synthetic T.

Multi-Anti-Parasitic Activity of Arylidene Ketones and Thiazolidene Hydrazines against Trypanosoma cruzi and Leishmania spp.

A series of fifty arylideneketones and thiazolidenehydrazines was evaluated against and . Furthermore, new simplified thiazolidenehydrazine derivatives were evaluated against . The cytotoxicity of the active compounds on non-infected fibroblasts or macrophages was established in vitro to evaluate the selectivity of their anti-parasitic effects.

Potent and Selective Inhibitors of Trypanosoma cruzi Triosephosphate Isomerase with Concomitant Inhibition of Cruzipain: Inhibition of Parasite Growth through Multitarget Activity.

Triosephosphate isomerase (TIM) is an essential Trypanosoma cruzi enzyme and one of the few validated drug targets for Chagas disease. The known inhibitors of this enzyme behave poorly or have low activity in the parasite. In this work, we used symmetrical diarylideneketones derived from structures with trypanosomicidal activity.