<jats:title>Abstract</jats:title><jats:p>Cyclomarins are highly potent antimycobacterial and antiplasmodial cyclopeptides isolated from a marine bacterium (Streptomyces sp.). Previous studies have identified the target proteins and elucidated a novel mode of action, however there are currently only a few studies examining the structure–activity relationship (SAR) for both pathogens. Herein, we report the synthesis and biological evaluation of 17 novel desoxycyclomarin‐inspired analogues. Optimization via side chain modifications of the non‐canonical amino acids led to potent lead structures for each pathogen.