Wollamide B is a cationic antimycobacterial cyclohexapeptide that exhibits activity against Mycobacterium bovis (M. bovis) (IC50 of 3.1 μM). Aiming to define its structural activity relationship (SAR), optimizing potency and pharmacokinetic properties, libraries of analogues were synthesized following a standard Fmoc-based solid phase peptide synthesis approach. The antimycobacterial activities of wollamide B and all the synthesized analogues were tested against Mycobacterium tuberculosis (Mtb) H37Rv. Parallely, in vitro drug metabolism and pharmacokinetic (ADME) profiling was done for the synthesized compounds to evaluate their drug likeness. Among the 25 synthesized wollamides five of them showed potent activities with MICs ≤ 3.1 μM and found to be nontoxic against human HepG2 cells up to 100 μM. The results of the in vitro ADME profiling revealed the remarkable plasma stability and very good aqueous solubility of the class in general while the metabolic stability was found to be moderate to low. Of particular note, compounds 7c (MIC = 1.1 μM) and 13c (0.6 μM) that exhibited good balance of antimycobacterial activity vs. optimal pharmacokinetic properties could be used as a new lead for further development.

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Viele Hürden erschweren die Forschung nach neuen Antituberkulotika. Nicht nur neue Substanzen werden dringend benötigt, auch die Kriterien zur Bewertung, neue Tiermodelle und Biomarker sind unumgänglich. Die schon vielversprechende Pipeline ist ein Ergebnis vieler Initiativen in der TB‐Forschung, vor allem die Arbeit der Private‐Public‐Partnerships leistet einen großen Beitrag, neue Substanzen in die Pipeline zu “befördern”. Zum Glück scheint auch die Industrie “erwacht”, an Tuberkulose zu forschen, wie ein sprunghafter Anstieg der Firmenpatente mit dem Thema Tuberkulose in den letzten acht Jahren zeigt. Der aussichtsreichste Wirkstoff in der Pipeline ist derzeit TMC207 (Bedaquilin).