ORIGINAL RESEARCH Synthesis and activity of (+)-usnic acid and (2)-usnic acid derivatives containing 1,3-thiazole cycle against Mycobacterium tuberculosis Olga B. Bekker • Dmitry N. Sokolov • Olga A. Luzina • Nina I. Komarova • Yuriy V. Gatilov • Sofia N. Andreevskaya • Tatiana G. Smirnova • Dmitry A. Maslov • Larisa N. Chernousova • Nariman F. Salakhutdinov • Valery. N. Danilenko Received: 25 June 2014 / Accepted: 19 February 2015 Ó Springer Science+Business Media New York 2015 Abstract New usnic acid (UA) derivatives were inves- tigated in vitro to elucidate their potential inhibitory ac- tivities on the growth of Mycobacterium smegmatis and Mycobacterium tuberculosis. Seven pairs of enantiomers of thiazole UA derivatives were tested using the M. smeg- matis strain mc 2 155 test system, and the ‘‘structure–ac- tivity’’ relationship was established. The most active compounds were (1)-3 and (2)-3, and their kinase in- hibitory activities were investigated. The results obtained using the Streptomyces lividans APHVIII? and M. smeg- matis APHVIII? test systems indicated the significant protein kinase activity of these compounds and revealed the species specificity of the actions of the dextro- and levorotatory isomers. Both isomers, (1)-3 and (2)-3, possess similar inhibitory activity against M. tuberculosis H37Rv. The action of the isomers on eukaryotic cells was also investigated, and the results demonstrate that the dextrorotatory isomer (1)-3 leads to the lysis of intact macrophages to a degree higher than that obtained spon- taneously and significantly higher than that obtained with the levorotatory isomer. Keywords Thiazole  Usnic acid  Tuberculosis  Mycobacterium smegmatis  Mycobacterium tuberculosis  Protein kinase activity  Inhibitory activity Introduction Tuberculosis (TB) annually kills approximately 2–3 million people worldwide. Approximately one-third of the world’s population is infected with TB, which may be latent for many years (and often for life) without the appearance of clinical symptoms (World Health Organization, 2012). Obviously, the development of a drug therapy for common diseases, such as TB, is of paramount importance for the medical and phar- maceutical industries. This situation is exacerbated by the fact that the emergence and spread of new drugs is regularly ac- companied by the sequential emergence of resistant forms of Mycobacterium (Udwadia, 2012; Prozorov et al., 2012; Casali et al., 2012). It has long been known that one of the difficulties associated with the treatment of tuberculosis is the emergence of M. tuberculosis with multidrug resistance (MDR) against both the traditional, i.e., the so-called first-line, antitubercu- losis drugs (particularly rifampicin and isoniazid) and second- line drugs (fluoroquinolones and aminoglycosides). Since approximately 8 years ago, when the anti-TB drugs began to be used for the treatment of patients with MDR isolates, cases of tuberculosis caused by strains with so-called extensively drug-resistant (XDR, extensive drug resistance) have been reported. This definition applies to strains that are resistant to at least two main ‘‘first-line’’ drug therapies, namely isoniazid and rifampicin, one of the fluoroquinolones, and one of three Electronic supplementary material The online version of this article (doi:10.1007/s00044-015-1348-2) contains supplementary material, which is available to authorized users. O. B. Bekker  D. A. Maslov  Valery. N. Danilenko Vavilov Institute of General Genetics, Russian Academy of Sciences, Gubkin str., 3, 119991 Moscow, Russia D. N. Sokolov  O. A. Luzina (&)  N. I. Komarova  Y. V. Gatilov  N. F. Salakhutdinov N. N. Vorozhtzov Novosibirsk Institute of Organic Chemistry of the Siberian Branch of Russian Academy of Sciences, Lavrent’eva ave., 9, 630090 Novosibirsk, Russia e-mail: luzina@nioch.nsc.ru S. N. Andreevskaya  T. G. Smirnova  L. N. Chernousova Federal State Budgetary Institution ‘‘Central Tuberculosis Research Institute’’ under the Russian Academy of Medical Sciences, Yauzskaya alley, 2, 107564 Moscow, Russia 123 Med Chem Res DOI 10.1007/s00044-015-1348-2 MEDICINAL CHEMISTR Y RESEARCH