Syntéza a studium vztahů mezi strukturou a antimykobakteriální aktivitou dinitrobenzylsulfanyl heteroaromátů

Univerzita Karlova v Praze Farmaceutická Fakulta v Hradci Králové Katedra anorganické a organické chemie Řešitel: Ing. Galina Karabanovich Školitel: Prof. PharmDr. Alexandr Hrabálek, CSc. Konzultant: PharmDr. Jaroslav Roh, Ph.D. Název disertační práce: Syntéza a studium vztahů mezi strukturou a antimykobakteriální aktivitou dinitrobenzylsulfanyl heteroaromátů Cíle této práce spočívají v designu a syntéze nových heteroaromatických sloučenin vykazujících vysokou a selektivní antimykobakteriální aktivitu a ve studiu vztahů mezi strukturou těchto látek a jejich antimykobakteriální účinností. V úvodu práce je shrnuta historie studia tuberkulózy (TB) a vývoje antituberkulotických léčiv, hledání vhodné terapie pro její léčbu a etiologie hlavního původce Mycobacterium tuberculosis (M.tb). Dále je v úvodu popsán současný stav epidemie TB a nové možnosti v její léčbě. Další kapitola je věnována struktuře mykobakteriální buněčné stěny, důležitého a charakteristického strukturálního rysu mykobakterií, díky které jsou mykobakterie vysoce odolné vůči vnějším vlivům a která je nezbytná pro růst a přežití M.tb. v organismu hostitele. Syntéza cílových látek, strategie prováděných strukturálních změn a výsledky antimykobakteriálních hodnocení připravených látek jsou popsány v kapitole 7. V rámci této práce byly...Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate: Ing. Galina Karabanovich Supervisor: Prof. PharmDr. Alexandr Hrabálek, CSc. Consultant: PharmDr. Jaroslav Roh, Ph.D. Title of PhD thesis: Synthesis and structure-antimycobacterial activity relationship study of dinitrobenzylsulfanyl heteroaromates This thesis deals with the design and synthesis of novel heterocyclic compounds with high and selective antimycobacterial activity and the structure - antimycobacterial activity relationship study of these compounds. The history of knowledge about Tuberculosis, drug/regimen development, a way to successfully understand the Mycobacterium tuberculosis (M.tb.) etiology and the search for suitable therapy for treatment of drug-susceptible and drug-resistant TB are described in chapters 2 and 3. The current situation of TB epidemic and efforts towards its solution are also included. In chapter 4, the structure of mycobacterial cell wall is presented. It demonstrates the mycobacterial structural feature possessing an unusual, highly protective properties, which is essential for M.tb. growth and its survival in the host. The synthesis, logical consistency of structural changes and the results of antimycobacterial evaluation of prepared...Katedra organické a bioorganické chemieDepartment of Organic And Bioorganic ChemistryFarmaceutická fakulta v Hradci KrálovéFaculty of Pharmacy in Hradec Králov

Synthesis and structure-antimycobacterial activity relationship study of dinitrobenzylsulfanyl heteroaromates

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate: Ing. Galina Karabanovich Supervisor: Prof. PharmDr. Alexandr Hrabálek, CSc. Consultant: PharmDr. Jaroslav Roh, Ph.D. Title of PhD thesis: Synthesis and structure-antimycobacterial activity relationship study of dinitrobenzylsulfanyl heteroaromates This thesis deals with the design and synthesis of novel heterocyclic compounds with high and selective antimycobacterial activity and the structure - antimycobacterial activity relationship study of these compounds. The history of knowledge about Tuberculosis, drug/regimen development, a way to successfully understand the Mycobacterium tuberculosis (M.tb.) etiology and the search for suitable therapy for treatment of drug-susceptible and drug-resistant TB are described in chapters 2 and 3. The current situation of TB epidemic and efforts towards its solution are also included. In chapter 4, the structure of mycobacterial cell wall is presented. It demonstrates the mycobacterial structural feature possessing an unusual, highly protective properties, which is essential for M.tb. growth and its survival in the host. The synthesis, logical consistency of structural changes and the results of antimycobacterial evaluation of prepared..

Development of 3,5-Dinitrobenzylsulfanyl-1,3,4-oxadiazoles and Thiadiazoles as Selective Antitubercular Agents Active Against Replicating and Nonreplicating Mycobacterium tuberculosis

Herein, we report the discovery and structure activity relationships of 5-substituted-2-[(3,5-dinitrobenzyl)-sulfanyl]-1,3,4-oxadiazoles and 1,3,4-thiadiazoles as a new class of antituberculosis agents. The majority of these compounds exhibited outstanding in vitro activity against Mycobacterium tuberculosis CNCTC My 331/88 and six multidrug-resistant clinically isolated strains of M. tuberculosis, with minimum inhibitory concentration values as low as 0.03 mu M (0.011-0.026 mu g/mL). The investigated compounds had a highly selective antimycobacterial effect because they showed no activity against the other bacteria or fungi tested in this study. Furthermore, the investigated compounds exhibited low in vitro toxicities in four proliferating mammalian cell lines and in isolated primary human hepatocytes. Several in vitro genotoxicity assays indicated that the selected compounds have no mutagenic activity. The oxadiazole and thiadiazole derivatives with the most favorable activity/toxicity profiles also showed potency comparable to that of rifampicin against the nonreplicating streptomycin-starved M. tuberculosis 18b-Lux strain, and therefore, these derivatives, are of particular interest