The incidence of life-threatening infections caused by multi-drug resistant Gram-positive and Gram-negative bacteria, as well as mycobacteria, is rapidly increasing. The discovery of new targets and the development of new antibacterials is therefore essential. DNA gyrase and to-poisomerase IV are validated targets for the development of new antibacterial agents. Their high structural similarity, enables the design of compounds that can simultaneously inhibit both enzymes. This can be an advantage in the battle against bacterial resistance.
In the framework of the doctoral dissertation, we synthesized and biochemically and micro-biologically evaluated new ATP-competitive inhibitors of the bacterial enzymes DNA gyrase (GyrB) and topoisomerase IV (ParE) with an extended spectrum of activity against problema-tic bacterial strains from the »ESKAPE« group. A series of compounds with low nanomolar inhibition of GyrB and ParE and strong antibacterial activity against Gram-positive (MIC va-lues of the most potent compound: <0,07–0,14 µM) and Gram-negative bacteria (MIC values of the most potent compound: 9–35 µM) has been prepared. Based on the structure of the hit compounds, which we have identified during screening of the library of ATP-competitive benzothiazole-type topoisomerase inhibitors of M. tuberculosis H37Rv, compounds with po-tent antibacterial activity against M. tuberculosis H37Rv and non-tuberculous M. abscessus RIVM were designed and prepared. The compounds exhibit a favorable safety profile and act selectively on mycobacteria. Such compounds do not contribute to the development of gene-ral antibacterial resistance and do not destroy the microflora.
The need for stereochemically pure intermediates and active pharmaceutical ingredients en-courages the development of asymmetric synthetic approaches to the stereomerically pure molecules. In this doctoral thesis we present the development of a method that enables access to CF3-substituted syn-1,2-diols. Reductive dynamic kinetic resolution with Noyori–Ikariya ruthenium catalysts was employed for the reduction of (het)aryl, benzyl, vinyl and alkyl ke-tones to the corresponding syn-1,2-diols via racemic α-hydroxyketones in a mixture of formic acid and triethylamine, with ⡥99% ee and ⡥87:13 syn/anti. The absolute configuration was asigned on the basis of single-crystal X-ray diffraction analysis. Density functional theory calculations have confirmed the hydrogen bond between the SO2 group of the catalyst and the hydrogen bond donor on the α-stereocenter of the ketone substrate in the hydrogen-transfer transition state. This method enables rapid access to stereomerically pure bioactive compounds. We have prepared analogues of the benzothiazole-cored topoisomerase inhibitor ULD1 with a CF3-syn-1,2-diol fragment and thus demonstrated its use as possible buliding block of complex molecules.
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