Synthesis and Evaluation of Antimycobacterial and Antiplasmodial Activities of Hirsutellide A and Its Analogues.

Hirsutellide A is nature-derived cyclic hexadepsipeptide with reported antimycobacterial and antiplasmodial activities. To verify its structure, hirsutellide A was synthesized following a solution-phase peptide synthesis approach. A detailed analysis of the H and C NMR spectra of the synthesized compound revealed structural variation from what had been originally assigned for hirsutellide A, despite the use of identical building blocks. This variation occurred at the two -Ile moieties. To investigate the structure-activity relationship, the depsipeptide and peptide analogues of hirsutellide A were prepared and tested for antimycobacterial and antiplasmodial activities. The compounds displayed antiplasmodial potency against 3D7 while showing weak or no activity against H37Rv. The drug-likeness of the series was assessed through absorption, distribution, metabolism, and excretion (ADME) profiling, revealing systematic differences between the pharmacokinetic properties of cyclic hexapeptides and hexadepsipeptides.