In this review, we present the potential use of the heterocyclic oxadiazole rings in the design and synthesis of new drugs to treat parasitic infections. We intend to compare herein all the four isomeric forms of oxadiazole rings as well as discuss the differences and similarities between them. In addition, we discuss aspects on their reactivity that justify the great importance of both 1,2,4-and 1,3,4-oxadiazoles isomers when compared with their other two isomers. Although some oxadiazole isomers satisfy Hückel's rule, there are differences concerning their aromaticity, which have a great impact on the possible interactions of the oxadiazole ring with biological receptors. The set of works selected from the literature and discussed herein points out the oxadiazole core as an important and versatile scaffold in the development of new chemical entities potentially useful as antiparasitic drugs.

A series of 3-substituted-7-aminoalcoxy-coumarin was designed and evaluated as cholinesterase inhibitors and antioxidants. All compounds were effective in inhibiting AChE with potencies in the nanomolar range. The 3-(4-(dimethylamino)phenyl)-7-aminoethoxy-coumarin (6a) was considered a hit, showing good AChE inhibition potency (IC50 = 20 nM) and selectivity (IC50 BuChE/AChE = 354), quite similar to the reference drug donepezil (IC50 = 6 nM; IC50 BuChE/AChE = 365), also presenting antioxidant properties, low citotoxicity and good-predicted ADMET properties. The mode of action (mixed-type) and SAR analysis for this series of compounds were described by means of kinetic and molecular modeling evaluations.

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Cancer and parasitic diseases, such as leishmaniasis and Chagas disease, share similarities that allow the co-development of new antiproliferative agents as a strategy to quickly track the discovery of new drugs. This strategy is especially interesting regarding tropical neglected diseases, for which chemotherapeutic alternatives are extremely outdated. We designed a series of (E)-3-aryl-5-(2-aryl-vinyl)-1,2,4-oxadiazoles based on the reported antiparasitic and anticancer activities of structurally related compounds. The synthesis of such compounds led to the development of a new, fast, and efficient strategy for the construction of a 1,2,4-oxadiazole ring on a silica-supported system under microwave irradiation. One hit compound (23) was identified during the in vitro evaluation against drug-sensitive and drug-resistant chronic myeloid leukemia cell lines (EC50 values ranging from 5.5 to 13.2 µM), Trypanosoma cruzi amastigotes (EC50 = 2.9 µM) and Leishmania amazonensis promastigotes (EC50 = 12.2 µM) and amastigotes (EC50 = 13.5 µM). In silico studies indicate a correlation between the in vitro activity and the interaction with tubulin at the colchicine binding site. Furthermore, ADMET in silico predictions indicate that the compounds possess a high druggability potential due to their physicochemical, pharmacokinetic, and toxicity profiles, and for hit 23, it was identified by multiple spectroscopic approaches that this compound binds with human serum albumin (HSA) via a spontaneous ground-state association with a moderate affinity driven by entropically and enthalpically energies into subdomain IIA (site I) without significantly perturbing the secondary content of the protein.

Nitroimidazoles are pharmacophoric groups responsible for important antiparasitic activity against several infectious diseases. 2-Nitroimidazoles are found in some antiparasitic drugs and are one of the main moieties responsible for the biological activities exhibited. As an example, we can mention the drug benznidazole, the only drug available in Brazil for the treatment of Chagas disease. This work describes an efficient methodology for the synthesis of 2-nitro-1-vinyl-1H-imidazole through a simple and direct approach, as well as its full characterization and biological assessment. The antiparasitic evaluation of 2-nitro-1-vinyl-1H-imidazole against Trypanosoma cruzi (Tulahuen C2C4-LacZ strain) showed IC50 = 4.8 μM on amastigotes and low cytotoxicity against LLC-MK2 cells (IC50 > 500 μM), validating 2-nitro-1-vinyl-1H-imidazole as a biologically active structural subunit for anti-T. cruzi activity. The results presented herein demonstrate that 2-nitro-1-vinyl-1H-imidazole can be easily obtained, possessing great potential for use in the design of new antichagasic drugs through a molecular hybridization strategy using known coupling reactions.