Vpliv bioizosterne zamenjave osrednje fenilne skupine na zaviralno delovanje encima InhA pri tetrahidropiranskem tipu zaviralcev : industrijska farmacija

Novak, Janja (author), Pajk, Stane (mentor)

Bakterijska okužba z M.tuberculosis lahko povzroči tuberkulozo, bolezen, ki v večini primerov prizadane pljuča, lahko pa tudi ostale organe. V nekaterih primerih je lahko tudi smrtna. Standardno zdravljenje poteka s protibakterijskimi učinkovinami, natančneje z izoniazidom ali več učinkovinami hkrati (rifampicin, etambutol). Za učinkovito zdravljenje tuberkuloze je potrebno sočasno jemanje več zdravil. Čeprav se je pojavnost in smrtnost bolezni v zadnjih letih močno zmanjšala, je ta napredek pogosto spregledan zaradi naraščanja razširjenosti okužb z večkrat odpornimi bakterijami tuberkuloze ali še hujše oblike rezistence. Zaradi odpornosti določenih sevov na obstoječe metode zdravljenja se razvijajo nove oblike zdravilnih učinkovin za zdravljenje tuberkuloze, gre za t.i. direktne zaviralce encima InhA: tetrahidropiranski derivati, triklosan, piridomicin, 4-hidroksi-2-piridoni, tiadiazoli. Pri eksperimentalnem delu smo se osredotočili na bioizosterno zamenjavo osrednje fenilne skupine na tetrahidropiranskem tipu InhA zaviralcev. S pomočjo obročnih ekvivalentov smo fenilni obroč zamenjali s tiofenom in tiazolom. Med eksperimentalnim delom smo se srečali z določenimi tipi reakcij, kot npr.: radikalno halogeniranje – bromiranje; redukcijo nitrilov do aminov; sklopitvenimi reakcijami, kjer se je tvoril karboksamid. Uspeli smo sinetizirati dve končni spojini: spojino 8: 5-((3,5-dimetil-1H-pirazol-1-il)metil)-N-((4-(4-feniltiazol-2-il)tetrahidro-2H-piran-4-il)metil)tiofen-2-karboksamid in spojino 16: 2-((3,5-dimetil-1H-pirazol-1-il)metil)-N-((4-(4-feniltiazol-2-il)tetrahidro-2H-piran-4-il)metil)tiazol-4-karboksamid. Po končani sintezi smo analizirali končne spojine z jedrsko magnetno resonanco (1H,13C) in masno spektrometrijo visoke ločljivosti. Preverili smo tudi čistost dobljenih spojin s tekočinsko kromatografijo visoke ločljivosti. Končnim spojinam so na encimu InhA določili vrednost zaviralne koncentracije (IC50) na encimu. Glede na rezultate analiz se je tiofen izkazal za ustreznejšo zamenjavo fenila. Uspelo nam je pripraviti bolj čist tetrahidropiranski deriavat s tiofenom kot s tiazolom, poleg tega je izkazal tudi nižjo IC50 vrednost od tiazola.

• Language: Slovenian
• Keywords: direktni zaviralci Inh tetrahdripiranski derivat bioizosterna zamenjava sinteza spojin, sinteza dela b tiazoli
• Work type: Master's thesis/paper
• Typology: 2.09 - Master's Thesis
• Organization: FFA - Faculty of Pharmacy
• Place of publishing: Ljubljana
• Publisher: [J. Novak]
• Year: 2018
• Number of pages: VII, 53 f.
• PID: 20.500.12556/RUL-120266
• UDC: 616-002.5+-616-085(043.3)
• COBISS.SI-ID: 4645489
• Publication date in RUL: 17.09.2020

Secondary language

• Language: English
• Title: Effect of bioisosteric replacement of central phenyl group on the inhibitory activity of the tetrahydropiran type InhA inhibitors

Abstract

The bacterial infection with M.tuberculosis can cause tuberculosis, a disease that in most cases affects the lungs, but it can also affect other organs. Sometimes, it can also be deadly. The standard treatment uses antibacterial substances, specifically isoniazid or more substances at the same time (rifampicin, etambutol). For an effective treatment, it is necessary to take several medications simultaneously. Although the incidence and mortality of the disease lowered in the last years, this achievement is often overlooked because of increasing infections with multiple drug-resistant M. tuberculosis or an even worse form of resistance. Due to the resistance of strains to the existing methods of treatment, new forms of active substances for treatment of tuberculosis are being developed, these are direct inhibitors of enzyme InhA: tetrahydropyran derivatives, triclosan derivatives, pyridomycin, 4-hydroxy-2-pyridones, thiadiazoles. In the experimental part of our work, we focused on the effect of bioisosteric replacement of central phenyl group on the inhibitory activity of the tetrahydropiran type InhA inhibitors. With the help of ring equivalents, we replaced phenyl group with thiophene and thiazole. During this part of our work, we encountered a certain type of reactions, e.g. radical halogenation – bromination, reduction of nitriles to amines and coupling reactions. We synthesized two final compounds: compound 8: 5-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N((4-(4-phenylthiazol-2-yl)tetrahydro-2Hpyran-4-yl)methyl)thiophene-2-carboxamide, and compound 16: 2-((3,5-dimethyl-1H-pyrazol-1yl)methyl)-N-((4-(4-phenylthiazol-2yl)tetrahydro-2H-pyran-4yl)methyl)thiazole-4-carboxamide. After the synthesis was completed, we analyzed the final compounds with nuclear magnetic resonance and high resolution mass spectrometry. We also checked the purity of the compounds with high performance liquid chomatography. The final compounds were tested on encyme InhA for the values of IC50. Based on the results of the analysis, tiophene proved to be the better replacement of phenyl. We also managed to prepare a purer tetrahydropyran derivative with thiophene than with thiazole and it showed a lower IC50 value than tiazol.

• Keywords: tuberculosis direct InhA inhibitors tetrahydropyran derivatives bioisosteric replacement.