Executive Summary: One of the strongest lines of research developed in our laboratory focuses on the search for new molecules that present biological activity. Among the different compounds that we are studying are bispirazol-5-ones, which have shown activity against Leishmania mexicana promastigotes and good antioxidant activity in vitro.
These molecules can be used as a starting product to obtain bis(spiro-2,4-dihydro-3H-pyrazol-3-one) cyclopropanes, which are heterocycles that have a spirocyclopropane in their structure. Molecules that incorporate a ring of these characteristics have received considerable attention, since they exhibit a wide range of biological activities such as antibiotic, antitumor, antiviral, and enzyme inhibitors, among others. A structural analysis of the active principles of medicines that are currently on the market shows that several of them incorporate this cycle. Some are in high demand, such as montelukast and ciprofloxacin. Another case is that of the drug ledipasvir, which is used for the treatment of hepatitis C and presents a spirocillopropane attached to a nitrogenous heterocycle.
Despite these precedents, there are not many studies on the activity of molecules that present spirocycles of the mentioned type. Thus, in existing reports, it can be seen that these compounds act as non-nucleoside inhibitors of HIV-1 reverse transcriptase, L-fucosidase and β-lactamase. But, in the specific case of bis(spiro-2,4-dihydro-3H-pyrazol-3-one) cyclopropanes, there is only one report that refers to the inhibitory activity of advanced glycation products (AGEs) for the treatment of schizophrenia.
Due to the background that we have on the bioactivity of bispyrazoles and their great structural similarity with derived spirocyclopropanes, the research proposal that we carry out intends to continue with the study of the bioactivity of these compounds and, likewise, proposes synthesizing a series of bis(spiro-2,4-dihydro-3H-pyrazol-3-one) cyclopropanes to evaluate their leishmanicidal and/or antitumor activity; as well as determine its mechanism of action (antioxidant, cytotoxic and/or interference with DNA replication).
Objectives General: To evaluate the antioxidant, cytotoxic, leishmanicidal and genotoxic activities of spirocyclopropanes derived from 4,4´-(arylmethylene)-bis-(1-phenyl-3-methyl-1H-pyrazole-5-ols).
Specific objectives:
- Synthesize bis(spiro-2,4-dihydro-3H-pyrazol-3-one)cyclopropanes from 4,4´-(arylmethylene)-bis-(1-phenyl-3-methyl-1H-pyrazol-5-ols ).
- To evaluate the in vitro activity of bis(spiro-2,4-dihydro-3H-pyrazol-3-one) cyclopropanes against Leishmania mexicana and various human tumor cell lines: cerebral astrocytoma (D-384), grade IV prostatic adenocarcinoma (PC -3), breast adenocarcinoma (MCF-7), human colon carcinoma (RKO) and lung carcinoma (A-549); in addition to normal cells.
- To determine the possible modes of action (antioxidant, interference with DNA replication) of bis(spiro-2,4-dihydro-3H-pyrazol-3-one) cyclopropanes.
Participating Institutions:
UTE, UCE, UTPL.
Participants:
Project manager Jorge Humberto Heredia Moya.
- Jorge Humberto Heredia Moya
- Patricio Rojas Silva
- Olalla Barreiro Costa
- Ana Maria Poveda Gabaldon
- Javier Santamaria Aguirre
- Karen Elena Tufiño Geacoman
- Jorge Esteban Perez Barrera
- Rommel Emilio Guevara Santander
- Juan Jaime Quinatoa Jami
- Juan Carlos Romero Benavides
- Natalia Catalina Bailon Moscoso
Awarded budget: $50000
Project status: In progress.
