Design and Synthesis of Macrocyclic Scaffolds for Compounds with Potential Antituberculosis/Antibacterial Activity and Improved CYP450 Properties

Based on an earlier suggested general pharnacophore approach, compounds active against tuberculosis virulent strain H37Rv were obtained. The main drawback of these compounds was an almost complete CYP 3A4 inhibition, which presumably could be overcome by macrocyclization. Three 15-16-membered macrocyclic scaffolds with pharmacophore groups located in appropriate positions were designed and synthetic schemes for their achievement were elaborated. Testing of these compounds against CYP450 enzymes confirmed generally lower inhibition of key cytochromes CYP 3A4 and CYP2D6 by the macrocyclic compounds compared to acyclic prototypes.