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dc.contributor.advisorCarballeira, Nestor M.
dc.contributor.authorAlequin Torres, Denisse
dc.date.accessioned2021-07-07T21:03:12Z
dc.date.available2021-07-07T21:03:12Z
dc.date.issued2021-01-29
dc.identifier.urihttps://hdl.handle.net/11721/2509
dc.description.abstractMarine sponges and anemones have provided most of the naturally occurring halogenated vinylic fatty acids (FA) known to date. Red algae such as <em>A. taxiformis</em> and <em>Bonnemaisonia nootkana</em> biosynthesize interesting brominated and chlorinated FA. Some of these compounds exhibit antifungal activity but their antiprotozoal and antibacterial activity remain unexplored.&nbsp;<br /> <br /> In this work we report the synthesis and characterization of a novel series of halogenated vinylic FA with different chain lengths: 2-allyl-3-bromo-2E-nonadecenoic acid (1a), 2-allyl-3-chloro-2E-nonadecenoic acid (2a), 2-allyl-3-bromo-2E-dodecenoic acid (1b), 2-allyl-3-chloro-2E-dodecenoic acid (2b), 2-allyl-3-bromo-2E-hexadecenoic acid (1c), and 2-allyl-3-chloro-2E-hexadecenoic acid (2c) in synthetically useful yields (38-83%), which allow us to study their potential as antileishmanial and antibacterial agents.&nbsp;<br /> <br /> The inhibitory effect of the FA&rsquo;s with the longest chain (19 carbons) 1a and 2a, and the ones with the shortest chain (12 carbons) 1b and 2b on LTopIB and hTopIB was explored. The brominated FA 1a displayed a higher inhibitory potential to both enzymes than the chlorinated analog (LTopIB EC<sub>50</sub> = 7.4 &plusmn; 0.2 &mu;M, hTopIB EC<sub>50</sub> = 12.7 &plusmn; 0.0 &mu;M). The reduction of the carbon chain length from 19 to 12 carbons (1b and 2b) proved detrimental. The mechanism of the inhibition of LTopIB by the halogenated vinylic FA 1a and 2a follows a Gimatecan-independent mechanism. The long-chain FA 1a and 2a also displayed higher toxicity towards amastigotes than towards promastigotes demonstrating that these FA can distinguish between the different stages of the leishmanial parasite and display differential toxicities towards each stage. Molecular modeling studies of 1a and 2a determined, that in fact, the brominated FA 1a forms a halogen bond (binding energy = -4.85 kcal/mol) with a DNA phosphate group and an ionic interaction between the carboxylate and Lys 262, which supports the higher potency of 1a (IC<sub>50</sub> = 7.4 &mu;M) over its chlorinated analog 2a (IC<sub>50</sub> = 25.7 &mu;M).&nbsp;<br /> <br /> The shorter chain FA&rsquo;s antibacterial potential was also studied (1b, 2b, 1c, and 2c) against 5 clinical isolates of methicillin-resistant <em>Staphylococcus aureus</em> (CIMRSA) strains. Using microdilution susceptibility testing, we determined that the most significant inhibition was obtained with brominated FA 1c for all five CIMRSA strains studied. Moreover, 1c showed inhibitory effects comparable to, and- on some occasions (as with CIMRSA XII and XIII), even better than Ciprofloxacin (Cipro). The brominated hexadecenoic acid 1c also displayed a 19% cytotoxicity against Vero Cells at 100 &mu;g/mL and in kinetic growth assays demonstrated to be toxic to CIMRSA XIII at a significantly lower concentration than Cipro (31.2 &mu;g/mL of 1c vs 250 &mu;g/mL of Cipro), which reveals the potency of 1c as an antibacterial agent towards CIMRSA strains. Our results indicate that the mechanism of action of 1c on the inhibition of these CIMRSA involves disrupting of the cell wall. We also determined that the brominated hexadecenoic FA inhibited the <em>norB</em> expression in <em>S. aureus</em>, suggesting that the bacteria is not resistant to 1c, which makes it a great antibacterial candidate.en_US
dc.language.isoen_USen_US
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/us/*
dc.subjectAntileishmanialen_US
dc.subjectHalogenated fatty acidsen_US
dc.subjectSynthesisen_US
dc.subject.lcshAntibacterial agentsen_US
dc.subject.lcshOrganohalogen compoundsen_US
dc.titleDevelopment of a novel series of vinylic halogenated fatty acids and their potential biomedical applications.en_US
dc.typeDissertationen_US
dc.rights.holder© 2021 Denisse Alequin Torresen_US
dc.contributor.committeeSanabria Rios, David J.
dc.contributor.committeeDiaz Vazquez, Liz M.
dc.contributor.committeePrieto, Jose A.
dc.contributor.campusUniversity of Puerto Rico, Río Piedras Campusen_US
dc.description.graduationSemesterSpring (2nd Semester)en_US
dc.description.graduationYear2021en_US
thesis.degree.disciplineChemistryen_US
thesis.degree.levelPh.D.en_US


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Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivs 3.0 United States