Carboxylic acid is one of the most common functional groups in drug molecules; however, its application is often limited by unfavourable pharmacokinetic properties. One approach to improve these properties is the bioisosteric replacement of the carboxylic acid moiety. In this master's thesis, this strategy was applied to the development of six bioisosteric analogues of the benzothiazole-based DNA gyrase inhibitor ULD1 and six bioisosteric analogues of probenecid as a pannexin 1 inhibitor. The carboxylic acid group was replaced with alcohol- and ketone-based bioisosteres, while a trifluoromethyl group was introduced into selected analogues. The compounds were synthesized using sodium borohydride reduction of ketones, nucleophilic addition of Grignard or Ruppert–Prakash reagents, benzothiazole ring formation using in situ generated thiocyanogen, and asymmetric catalytic hydrogenation.
The DNA gyrase inhibitors were evaluated against recombinant Escherichia coli DNA gyrase, and their antibacterial activity was determined against E. coli and Staphylococcus aureus strains. Compound 3 exhibited the highest inhibitory activity (IC50 = 0,64 μM), followed by compound 10. None of the compounds were active against E. coli. The strongest activity against S. aureus was observed for compound 11 (MIC = 64 μg/mL), most likely through a mechanism independent of DNA gyrase inhibition. Compound 10 was the only compound that inhibited DNA gyrase while also exhibiting antibacterial activity against S. aureus. The logD values and thermodynamic solubility of all compounds were also determined. Bioisosteric replacement increased lipophilicity and decreased solubility of the ULD1 analogues, whereas the probenecid analogues retained relatively favourable physicochemical properties. The trifluoromethyl ketone analogue 18 exhibited an unexpectedly low logD value and good solubility, most likely due to hydration to the corresponding geminal diol. The probenecid analogues were preliminarily evaluated in a THP-1 cell model by measuring interleukin-1β (IL-1β) release following stimulation with PAM3CSK4. At a concentration of 2 mM, all analogues reduced IL-1β release without increasing lactate dehydrogenase release, indicating that the observed effect was not due to cytotoxicity.
The results of this master's thesis demonstrate that bioisosteric replacement of the carboxylic acid moiety significantly affects the physicochemical properties of the compounds, with the outcome depending on the molecular scaffold and the selected biological target.
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