title: Design of novel camphane-based derivatives with antimycobacterial activity.
abstract: 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.
authors.affiliation: Faculty of Pharmacy, Medical University of Sofia, 2 Dunav st., Sofia 1000, Bulgaria.
authors.forename: Georgi
authors.initials: G
authors.lastname: Stavrakov
authors.affiliation: Institute of Microbiology, Bulgarian Academy of Sciences, 26 Akad. Bonchev st., Sofia 1113, Bulgaria.
authors.forename: Violeta
authors.initials: V
authors.lastname: Valcheva
authors.affiliation: Institute of Organic Chemistry, Bulgarian Academy of Sciences, 9 Acad. Bonchev st., Sofia 1113, Bulgaria.
authors.forename: Irena
authors.initials: I
authors.lastname: Philipova
authors.affiliation: Faculty of Pharmacy, Medical University of Sofia, 2 Dunav st., Sofia 1000, Bulgaria. Electronic address: idoytchinova@pharmfac.net.
authors.forename: Irini
authors.initials: I
authors.lastname: Doytchinova
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001892:Camphanes / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D006860:Hydrogen Bonding; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D001892:Camphanes
keywords: Antimycobacterial activity; Camphane-based derivatives; Drug design; QSAR; Tuberculosis