Design of novel camphane-based derivatives with antimycobacterial activity

• We designed nine new camphene-based derivatives following the guidelines derived in a previous QSAR study.
• The compounds were synthesized and tested against M. tuberculosis strain H37Rv.
• Four compounds showed activities in the nanomolar range.
• New QSAR study was performed to guide further lead optimization.

Although tuberculosis (TB) continues to be one of the leading infectious disease killers globally, it is curable and preventable. Despite the existence of safe, well tolerated and effective drugs used in the TB treatment, the interest in new entities, combinations and regimens increases during the last 10 years. Recently, we reported for a new class of anti-TB agents – camphane-based derivatives with nanomolar activity against Mycobacterium tuberculosis strains. The quantitative structure–activity relationship (QSAR) study on 12 compounds revealed several structural requirements for antimycobacterial activity: two hydrogen bond donors, two or three rings and no large branched substituents. Here, we describe the design of a set of nine novel camphane-based derivatives following these requirements. The compounds were synthesized and tested against M. tuberculosis strain H37Rv. Four of them showed activities in the nanomolar range, significantly higher than the activities in the initial set. The QSAR study based on all 21 derivatives pointed to two main structural requirements for anti-TB activity: two hydrogen bond donors and a side chain with aromatic ring.

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