- Synthesis and evaluation of new 2-aminothiophenes against: Mycobacterium tuberculosis
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Tuberculosis (TB) and its drug resistant forms kills more people than any other infectious disease. This fact emphasizes the need to identify new drugs to treat TB. 2-Aminothiophenes (2AT) have been reported to inhibit Pks13, a validated anti-TB drug target. We synthesized a library of 42 2AT compounds. Among these, compound 33 showed remarkable potency against Mycobacterium tuberculosis (Mtb) H37RV (MIC = 0.23 μM) and showed an impressive potency (MIC = 0.20-0.44 μM) against Mtb strains resistant to isoniazid, rifampicin and fluoroquinolones. The site of action for the compound 33 is presumed to be Pks13 or an earlier enzyme in the mycolic acid biosynthetic pathway. This inference is based on structural similarity of the compound 33 with known Pks13 inhibitors, which is corroborated by mycolic acid biosynthesis studies showing that the compound strongly inhibits the biosynthesis of all forms of mycolic acid in Mtb. In summary, these studies suggest 33 represents a promising anti-TB lead that exhibits activity well below toxicity to human monocytic cells.
- Thanna, Sandeep,Knudson, Susan E.,Grzegorzewicz, Anna,Kapil, Sunayana,Goins, Christopher M.,Ronning, Donald R.,Jackson, Mary,Slayden, Richard A.,Sucheck, Steven J.
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p. 6119 - 6133
(2016/07/06)
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- Tracing binding modes in hit-to-lead optimization: Chameleon-like poses of aspartic protease inhibitors
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Successful lead optimization in structure-based drug discovery depends on the correct deduction and interpretation of the underlying structure-activity relationships (SAR) to facilitate efficient decision-making on the next candidates to be synthesized. Consequently, the question arises, how frequently a binding mode (re)-validation is required, to ensure not to be misled by invalid assumptions on the binding geometry. We present an example in which minor chemical modifications within one inhibitor series lead to surprisingly different binding modes. X-ray structure determination of eight inhibitors derived from one core scaffold resulted in four different binding modes in the aspartic protease endothiapepsin, a well-established surrogate for e.g. renin and β-secretase. In addition, we suggest an empirical metrics that might serve as an indicator during lead optimization to qualify compounds as candidates for structural revalidation.
- Kuhnert, Maren,K?ster, Helene,Bartholom?us, Ruben,Park, Ah Young,Shahim, Amir,Heine, Andreas,Steuber, Holger,Klebe, Gerhard,Diederich, Wibke E.
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supporting information
p. 2849 - 2853
(2015/03/04)
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- 2-Aminothiophene-3-carboxylates and carboxamides as adenosine A1 receptor allosteric enhancers
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Three series of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene and 2-amino-5,6,7,8-tetrahydrocyclohepta[b]thiophenes with 3-carboxylates and carboxamides have been prepared using the Gewald synthesis and evaluated as A1AR allosteric enhancers. The
- Nikolakopoulos, George,Figler, Heidi,Linden, Joel,Scammells, Peter J.
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p. 2358 - 2365
(2007/10/03)
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