Synthesis and biological activities of petromurin C nitrile derivatives

A series of nitrile derivatives of Petromurin C were synthesized and assessed for their cytotoxic effects on tumor cell lines and inhibitory activity against Mycobacterium tuberculosis (M.tb H37Ra). Bromoalkyl nitriles (Br(CH2)nCN; n=1-5) and (o-, m-, p-) bromomethyl benzonitriles were used as alkylating reagents. The majority of the syntheses consisted of O-alkylated derivatives in which the two NH group were not alkylated, as expected from the treatment of petromurin C with K2CO3 in DMF followed by treatment with alkylating reagents. Similarly, treatment of Petromurin C with NaH in DMF and the treatment with alkylating reagents yielded both OR and bis-NR alkylated structures. In the first method, 7 different O-alkyl Petromurin C derivatives were obtained.  The second method yielded 7 different Petromurin-C derivatives containing both O-alkyl and bis-N-alkyl groups. Notably, compounds 1-4 and 7-10 demonstrated selective inhibitory activity against the acute myeloid leukemia cell line MV4-11, with IC50 values ranging from 12.96 to 20.00 μM. Compound 15 exhibited a minimum inhibitory concentration (MIC) of 6.25 μM against M.tb H37Ra. Importantly, all synthesized compounds showed negligible inhibition (below 50%) against human normal cell lines L-02 and 293T at a concentration of 100 μM. These findings suggest that the compounds possess high efficacy and low toxicity, indicating their potential as novel therapeutic agents for the treatment of leukemia and tuberculosis.