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Browsing Tesis Doctorado by Author "Arancibia González, Rodrigo Sebastián"
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Item Bases de Schiff organometálicas derivadas de sulfonamidas como potenciales agentes biológicos multifuncionales.(Universidad de Concepción, 2023) Gallardo Farías, Miguel Ángel; Arancibia González, Rodrigo SebastiánIn this Doctoral Thesis, framed in the Bioorganometallic Chemistry research line new bioorganometallic Schiff bases derived from sulfonamides were synthesized, characterized, and evaluated the multifunctional biological properties. The rational design involved connecting the ferrocenyl- and cymanthrenyl-sulfonyl fragments with different bioactive rings through various bridges and evaluating their antitumor, trypanocidal, and carbonic anhydrase inhibitory properties (Figure 1). Figure 1. General scheme of new bioorganometallic Schiff bases derived from sulfonamides. From the methodological point of view, the work included, in a first stage, the obtaining of the organometallic precursors of the type [(η5 -C5H4SO2NH-NH2)MLn] and [(η5 -C5H4SO2NH-bridge-NH2)MLn] (where MLn = FeCp, Mn(CO)3; bridge = - CH2CH2, -C6H4-) (p1-5), via substitution reactions. In a second stage, the organometallic Schiff bases were isolated by condensation reactions involving organic aldehydes or ketones with the p1-5 precursors. The compounds were divided into families of sulfonylhydrazones (without bridge) and sulfonyl imines (with aliphatic bridge) derived from of the nitro-heterocyclic (1a-d, 2a-d, 3a, 4a, 3c, 4c, 5a-c, 6a y 6c), from salicylaldehyde/2-hydroxyacetophenone (1f-i, 2f and 2h) and N-heterocyclic systems (1j-o, 2j and 2n), in good yields (60-80%). All synthesized compounds were characterized by conventional spectroscopic techniques and mass spectrometry. Structural analysis by X-ray diffraction of compounds 1a-b, 3a, 5a, 2b, 1d, 1h, 2h, 1l, 1n-o and 2n show an E configuration around the iminic bond. It is worth mentioning that the electrochemical properties of all precursors organometallic and the compounds derived from the nitro heterocyclic were studied using the cyclic voltammetry technique. Finally, the trypanocidal activity of Schiff bases derived from nitro-heterocyclic were evaluated in vitro against Trypanosoma cruzi (epimastigote and trypomastigote) and Trypanosoma brucei (trypomastigote). In this sense, it was established that: i) the compounds with cymanthrenyl fragment (1c EC50 = 13.0 μM) have a greater activity than their ferrocene analogues (1a EC50 = 31.2 μM); ii) nitro-thiophene derivatives (1a EC50 = 1.89 μM) are more active than nitrofuran derivatives (1b EC50 = 4.19 μM), except in T. cruzi (epimastigote) (1a EC50 = 19.3 µM and 1b EC50 = 18.9 µM); iii) the 5-nitro-heterocyclic derivatives were more active than their 4-nitro-heterocyclic counterparts for T. brucei (1a EC50 = 1.89 μM and 3a EC50 = >30 μM) and T. cruzi (epimastigote) (1a EC50 = 19.3 µM and 3a EC50 = 30.3 µM); iv) the addition of the methyl group decreases the activity in T. brucei (1a EC50 = 1.89 μM and 2a EC50 = 5.42 μM) and improves it in T. cruzi (1a EC50 = 19.3 μM and 2a EC50 = 12.6 µM); v) the addition of the aliphatic bridge decreases the activity (1c EC50 = 13.0 µM and 5c EC50 = 57.8 µM). Regarding the anticancer activity against the lung cancer cell lines H1299 and A549, only the organometallic compounds with the nitro-heterocyclic fragment showed activity. Of which the following relationships can be established: i) nitro furan derivatives (1b EC50 = 6.49 μM) are more active than nitro-thiophene derivatives (1a EC50 = 18.1 μM); ii) the compounds with the 5-nitro group have higher activity (1a EC50 = 18.1 μM and 3a EC50 = 71.8 μM); iii) the addition of the methyl group decreases the activity (1b EC50 = 6.49 μM and 2b EC50 = 14.5 μM); iv) The addition of the aliphatic bridge decreases the anticancer activity (1b EC50 = 6.49 µM and 5b EC50 = 50.8 µM). With respect to the evaluation as inhibitors of carbonic anhydrase, all Schiff bases were considered inactive since most of them presented Ki values greater than 100,000 nM. It is important to mention that, despite not being contemplated in the original proposal, a group of new organometallic sulfonamides with N-ethyl or N-methyl benzenesulfonamide units (S1a-b, S2a-b) were isolated by substitution reactions with low yields (S1a = 25%; S2a = 30%) to moderate (S1b = 45%; S2b = 49%). Biological evaluation as CA inhibitors (CAIs) showed that the S1a and S2a derivatives exhibit greater inhibition than the control drug (acetazolamide) for the hCA II and hCA IX isoforms (KI = 7.3 nM and 5.8 nM, respectively) and behave as selective inhibition of the hCA II isoform.