Sinteza derivatov 4-((3,5-dimetilpirazolil)metil)benzojske kisline kot potencialnih zaviralcev InhA : magistrska naloga

Lukan, Boštjan (author), Gobec, Stanislav (mentor), Živec, Matej (co-mentor)

Tuberkuloza je nalezljiva bolezen, ki jo povzroča okužba z bakterijo Mycobacterium tuberculosis, za katero letno na novo zboli okoli 9 milijonov ljudi, umre pa okrog 1,3 milijona ljudi, in je tako za AIDSom drugi najpogostejši vzrok smrti zaradi nalezljivih bolezni. Eden glavnih razlogov, da je bolezen tako trdovratna in ponovljiva, je odporna mikobakterijska celična ovojnica, ki vsebuje mikolne kisline. Izoniazid (INH), ki je eno od glavnih zdravil v boju proti tuberkulozi, deluje tako, da zavira delovanje encima InhA v FAS-II sistemu M. tuberculosis in s tem zavre sintezo mikolnih kislin, to pa povzroči nastanek sprememb v celični steni, ki vodijo v smrt patogena. INH je predzdravilo, ki ga v aktivno obliko pretvori encim KatG. V zadnjem desetletju postajajo čedalje večji problem na INH odporni sevi M. tuberculosis, pri katerih mutacija gena katG povzroča zmanjšano nastajanje encima katG, kar onemogoča oziroma zavira pretvorbo INH v aktivno obliko. Spojine, ki ne potrebujejo aktivacije s KatG in direktno zavirajo encim InhA, imajo tako velik potencial za razvoj novih učinkovin za boj proti rezistentnim sevom. GlaxoSmithKline (GSK) je s tehnologijo rešetanja visoke zmogljivosti nedavno odkril zanimive spojine, ki bi lahko predstavljale nova ogrodja za razvoj zaviralcev InhA. Z namenom, da bi raziskali razvojne možnosti in vzpostavili začetno razmerje med delovanjem in strukturo, smo sintetizirali nekaj derivatov enega izmed teh zadetkov (tetrahidropiranski derivat). V sklopu magistrskega dela smo sintetizirali 3-metoksifenilni derivat izhodne spojine, iz tega pa smo z demetilacijo poskusili sintetiziratii še 3-hidroksifenilni derivat. Iz dostopnih intermediatov smo pripravili tudi nekaj skrajšanih različno substituiranih analogov izhodne spojine brez tiazolnega obroča. Spojine smo nato poslali na testiranje zaviralnega delovanja na InhA in antibakterijskega delovanja na M. tuberculosis. Ker nobena izmed spojin ni pokazala izboljšanih rezultatov v primerjavi z začetno spojino, je naš sklep, da nadaljnji razvoj te spojine ni smiseln.

• Language: Slovenian
• Keywords: M. tuberculosis mikobakterijska celična ovojnica mikolne kisline InhA zaviralci InhA sinteza derivatov benzojske kisline
• Work type: Master's thesis/paper
• Typology: 2.09 - Master's Thesis
• Organization: FFA - Faculty of Pharmacy
• Place of publishing: Ljubljana
• Publisher: [B. Lukan]
• Year: 2015
• Number of pages: VII, 51 f.
• PID: 20.500.12556/RUL-81451
• UDC: 615.2:616-002.5(043.3)
• COBISS.SI-ID: 3838577
• Publication date in RUL: 11.04.2016

Secondary language

• Language: English
• Title: Synthesis of 4-((3,5-dimethylpyrazolyl)methyl)benzoic acid derivatives as potential InhA inhibitors

Abstract

Tuberculosis is an infectious disease caused by infection with Mycobacterium tuberculosis. About 9 million people get infected with this bacteria and 1.3 million die from the disease annually, which makes it the second most frequent cause of death by infectious diseases after AIDS. One of the main reasons for its persistence and repeatability is the resistant mycobacterial cell envelope, which contains mycolic acids. Isoniazid (INH), a frontline antitubercular drug, inhibits InhA enzyme in FAS-II system of M. tuberculosis, causing the mycolic acid synthesis to stop, which leads to alterations in the cell wall stability and pathogen death. INH is a prodrug activated by KatG enzyme. During the last decade, we have seen a growing problem of INH resistant M. tuberculosis strains, where the katG gene mutation leaded to reduced formation of KatG enzyme, causing the decreased conversion of INH to its active form. Compounds that do not need to be activated by KatG and inhibit InhA directly therefore show a great potential for development of new active substances against resistant strains. In a recent high-throughput screening campaign performed by GlaxoSmithKline (GSK), interesting compounds were identified that represent possible new scaffolds for InhA inhibitors. With the aim to assess their developability and to establish initial structure-activity relationship, we synthesized a focused library of derivatives structurally related to one of the hits (a tetrahydropyrane derivative). We synthesized 3-methoxyphenyl derivate of the initial compound, which we later on tried to convert to 3-hydroxyphenyl derivate through demethylation. We also synthesized some truncated and variously substituted analogues of the initial compound that lack the thiazole moiety, starting the synthesis from commercially available intermediates. The prepared compounds were then evaluated for their inhibition of InhA and for their antibacterial activity against M. tuberculosis. Since none of the compounds showed improved results comparing to hit inhibitor, our conclusion is that the starting compound is not a viable hit to be further investigated.