The number of worldwide deaths associated with infectious diseases is incresing. One of the main reasons for that is the developement of resistance of bacteria to available antibiotics and the decline in the number of new antibiotics entering the market that would be effective against resistant strains. Despite their frequent use in therapy and over half a century of research, beta-lactam antibiotics still represent an interesting
compound – for science, the industry and in treatment. Trinems are tricyclic carbapenems with very good antimicrobial activity. They are active against Grampositive and Gram-negative microorganisms by inhibiting enzymes responsible for the synthesis of peptidoglican – a crucial biopolymer and main constituent of the bacterial cell wall. In the thesis we used known trinemic compounds, sanfetrinem and LK-157, as leads for further development. In the first part, we designed and synthesized derivatives of LK-157 with the aim of achieving better activity against beta-lactamases and better pharmacokinetic properties. We have synthesized sodium salt of (8S,9R)-10-(E)-ethylidene-4-(S)-butoxy-11-oxo-azatricyclo[7.2.0.03,8]undec-2-en-carboxylate (LK170) and sodium salt of (8R,9R)-10-(E)-ethylidene-4-(R)-butoxy-11-oksoazatricyclo[ 7.2.0.03,8]undec-2-en-carboxylate (LK-171). The compounds are good inhibitors of class A beta-lactamases (especially LK-171 – IC50 = 12 nM), but with modest activity against class C beta-lactamases compared to lead compound. The crystal structure of the acylated complex of LK-171 with AmpC P99 revealed the main interactions between the enzyme and the inhibitor. In the second part, we wanted to modify the hydroxyethyl side chain, which is present in most clinicaly important carbapenems and most known trinems, substituting it with fluorine at the end of the ethyl chain. Starting with ethyl fluoroacetate, one of the most important synthetic steps was the stereo selective reduction of 2-benzamidomethyl-4-fluoro-3-oxo-butanoate into ethyl (2S,3S)-2-benzamidomethyl-4-fluoro-3-oxobutanoate with ee = 96 % and de = 66 %. This was achieved with the use of Ru-catalyzed asymmetric transfer hydrogenation. In subsequent steps, we transformed this intermediate to a synthetically useful precursor (1’S,3R)-4-acetoxy-3-[2’-fluoro-1’-trimethylsilyloxyethyl]-2-azetidinone, which is an interesting starting point for a variety of carbapenems or other derivatives with a beta-lactam structure. The final compounds of the second part were LK-180 – as sodium salt
of (4S,8S,9R,10S)-4-methoxy-10-[2-fluoro-1-(S)-trimethilsilyloxyethyl]-11-oxoazatricyclo-[7.2.0.03,8]undec-2-en-2-carboxylate and LK-181 as sodium salt of (8S,9R)-10-(E)-ethylidene-4-(S)-methoxy-11-oxo-azatricyclo[7.2.0.03,8]undec-2-en-carboxylate. LK-180 has a very good antibiotic activity against a broad spectrum of pathogenic bacteria, including strains which produce extended spectrum beta-lactamases. LK-180 is also a very good inhibitor of beta-lactamases, especially of the class C enzymes AmpCP99 (IC50 < 0.5 nM ). One of our goals was also an alternative synthesis of LK-180 which would be cheaper, have better yield and would be sutiable for scale-up. This produced a very interesting intermediate with a cyclic sulfate group - (1R,6S,9bR)-1-((1S)-2,2-dioxo-[1,3,2]-dioxathiolan-1-il)-6-methoxy-4,4-dimethyloctahydroazeto[1,2-
c]benzo[e][1,3]oxazin-2(4H)-one.
|
