A Novel Protocol for the Synthesis of 1,2,4-Oxadiazoles Active against Trypanosomatids and Drug-Resistant Leukemia
Paulo Pitasse-Santos1, Eduardo Salustiano2, Raynná Bittencourt Pena3
1Instituto de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica 23890-000, Rio de Janeiro, Brazil.
Abstract:
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is especially interesting regarding tropical neglected diseases, for which chemotherapeutic alternatives are extremely outdated.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.
Insights
New antiproliferative agents were developed for cancer and neglected parasitic diseases. A novel oxadiazole compound showed potent activity against leukemia, Chagas disease, and leishmaniasis, with promising druggability potential.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Parasitology
Background:
- Cancer and neglected parasitic diseases share biological pathways, enabling co-development of antiproliferative agents.
- Existing treatments for tropical neglected diseases are outdated, necessitating novel therapeutic strategies.
Purpose of the Study:
- To design and synthesize novel (E)-3-aryl-5-(2-aryl-vinyl)-1,2,4-oxadiazoles.
- To evaluate the antiproliferative and antiparasitic activities of these compounds.
- To investigate the mechanism of action and druggability potential of active compounds.
Main Methods:
- Synthesis of 1,2,4-oxadiazoles using a silica-supported system under microwave irradiation.
- In vitro evaluation against chronic myeloid leukemia cell lines, Trypanosoma cruzi, and Leishmania amazonensis.
- In silico studies including molecular docking and ADMET predictions.
- Spectroscopic analysis to determine compound-protein interactions.
Main Results:
- A novel, fast, and efficient synthesis strategy for 1,2,4-oxadiazoles was established.
- Compound 23 exhibited significant in vitro activity against drug-sensitive and resistant leukemia (EC50: 5.5–13.2 µM), T. cruzi (EC50: 2.9 µM), and L. amazonensis (EC50: 12.2–13.5 µM).
- In silico analysis suggested tubulin interaction at the colchicine binding site and favorable ADMET profiles.
- Compound 23 demonstrated moderate affinity binding to human serum albumin (HSA) in subdomain IIA.
Conclusions:
- The developed synthetic strategy is efficient for generating diverse 1,2,4-oxadiazoles.
- Compound 23 is a promising hit with broad-spectrum antiproliferative and antiparasitic activities.
- The identified compounds possess high druggability potential and a favorable interaction profile with HSA.
