The Role of Nitro (NO2-), Chloro (Cl), and Fluoro (F) Substitution in the Design of Antileishmanial and Antichagasic Compounds.

Neglected tropical diseases (NTDs) are responsible for over 500,000 deaths annually and are characterized by multiple disabilities. Leishmaniasis and Chagas diseases are among the most severe NTDs, and are caused by the Leishmania sp and Trypanosoma cruzi, respectively. Glucantime, pentamidine, and miltefosine are commonly used to treat leishmaniasis, whereas nifurtimox, benznidazole are current treatments for Chagas disease. However, these treatments are associated with drug resistance and severe side effects. Hence, the development of synthetic products, especially those containing N02, F, or Cl, are known to improve biological activity. The present work summarizes the information on the antileishmanial and antitrypanosomal activity of nitro-, chloro-, and fluorosynthetic derivatives. Scientific publications referring to halogenated derivatives in relation to antileishmanial and antitrypanosomal activities were hand-searched in databases such as SciFinder, Wiley, Science Direct, PubMed, ACS, Springer, Scielo, and so on. According to the literature information, more than 90 compounds were predicted as lead molecules with reference to their IC50/EC50 values in in vitro studies. It is worth mentioning that only active compounds with known cytotoxic effects against mammalian cells were considered in the present study. The observed activity was attributed to the presence of nitro-, fluoro-, and chloro-groups in the compound backbone. All in all, nitro and halogenated derivatives are active antileishmanial and antitrypanosomal compounds and can serve as the baseline for the development of new drugs against leishmaniasis and Chagas disease. However, efforts in in vitro and in vivo toxicity studies of the active synthetic compounds is still needed. Pharmacokinetic studies and the mechanism of action of the promising compounds need to be explored. The use of new catalysts and chemical transformation can afford unexplored halogenated compounds with improved antileishmanial and antitrypanosomal activity.

Unveiling the Targets Involved in the Quest of Antileishmanial Leads Using In silico Methods.

BACKGROUND: Leishmaniasis is a neglected tropical disease associated with several clinical manifestations, including cutaneous, mucocutaneous, and visceral forms. As currently available drugs have some limitations (toxicity, resistance, among others), the target-based identification has been an important approach to develop new leads against leishmaniasis. The present study aims to identify targets involved in the pharmacological action of potent antileishmanial compounds. METHODS: The literature information regarding molecular interactions of antileishmanial compounds studied over the past half-decade is discussed. The information was obtained from databases such as Wiley, SciFinder, Science Direct, National Library of Medicine, American Chemical Society, Scientific Electronic Library Online, Scopus, Springer, Google Scholar, Web of Science, etc. Results: Numerous in vitro antileishmanial compounds showed affinity and selective interactions with enzymes such as arginase, pteridine reductase 1, trypanothione reductase, pyruvate kinase, among others, which are crucial for the survival and virulence of the Leishmania parasite. CONCLUSION: The in-silico activity of small molecules (enzymes, proteins, among others) might be used as pharmacological tools to develop candidate compounds for the treatment of leishmaniasis. As some pharmacologically active compounds may act on more than one target, additional studies of the mechanism (s) of action of potent antileishmanial compounds might help to better understand their pharmacological action. Also, the optimization of promising antileishmanial compounds might improve their biological activity.

Flavones as a Privileged Scaffold in Drug Discovery: Current Developments.

BACKGROUND: Flavones are one of the main subclasses of flavonoids with diverse pharmacological properties. They have been reported to possess antimalarial, antimicrobial, anti-tuberculosis, anti-allergic, antioxidant, anti-inflammatory activities, among others. OBJECTIVE: The present review summarizes the recent information on the pharmacological properties of naturally occurring and synthetic flavones. METHODS: Scientific publications referring to natural and synthetic flavones in relation to their biological activities were hand-searched in databases such as SciFinder, PubMed (National Library of Medicine), Science Direct, Wiley, ACS, SciELO, Springer, among others. RESULTS: As per the literature, seventy-five natural flavones were predicted as active compounds with reference to their IC50 (<20 µg/mL) in in vitro studies. Also, synthetic flavones were found active against several diseases. CONCLUSION: As per the literature, flavones are important sources for the potential treatment of multifactorial diseases. However, efforts toward the development of flavone-based therapeutic agents are still needed. The appearance of new catalysts and chemical transformations is expected to provide avenues for the synthesis of unexplored flavones, leading to the discovery of flavones with new properties and biological activities.