Synthesis and NMR Elucidation of Novel Pentacycloundecane-Derived Peptides

Herein we report the synthesis and NMR elucidation of five novel pentacycloundecane (PCU)-derived short peptides as potential HIV protease inhibitors. 1H and 13C spectral analysis show major overlapping of methine resonance of the PCU ‘cage’ thereby making it extremely difficult to assign the NMR signals. Attachment of short peptides to the cage at position C-8/C-11 results in conformational differences of the peptide side chains due to diastereomeric interactions between the cage skeleton and the chiral side chains. The use of two-dimensional NMR techniques proved to be highly effective in the elucidation of such systems.Keywords: 1H NMR, 13C NMR, 2D NMR, PCU diol diaminoacid, HIV protease inhibitors PDF and supplementary file attached

Synergistic Interactions of Indole-2-Carboxamides and β-Lactam Antibiotics against Mycobacterium abscessus.

New drugs or therapeutic combinations are urgently needed against Mycobacterium abscessus Previously, we demonstrated the potent activity of indole-2-carboxamides 6 and 12 against M. abscessus We show here that these compounds act synergistically with imipenem and cefoxitin in vitro and increase the bactericidal activity of the β-lactams against M. abscessus In addition, compound 12 also displays synergism with imipenem and cefoxitin within infected macrophages. The clinical potential of these new drug combinations requires further evaluation

Novel linear Diamine disubstituted polycyclic "cage" derivatives as potential antimycobacterial candidates.

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Active Benzimidazole Derivatives Targeting the MmpL3 Transporter in Mycobacterium abscessus.

The prevalence of pulmonary infections due to nontuberculous mycobacteria such as Mycobacterium abscessus has been increasing and surpassing tuberculosis (TB) in some industrialized countries. Because of intrinsic resistance to most antibiotics that drastically limits conventional chemotherapeutic treatment options, new anti-M. abscessus therapeutics are urgently needed against this emerging pathogen. Extensive screening of a library of benzimidazole derivatives that were previously shown to be active against Mycobacterium tuberculosis led to the identification of a lead compound exhibiting very potent in vitro activity against a wide panel of M. abscessus clinical strains. Designated EJMCh-6, this compound, a 2-(2-cyclohexylethyl)-5,6-dimethyl-1H-benzo[d]imidazole), also exerted very strong activity against intramacrophage-residing M. abscessus. Moreover, the treatment of infected zebrafish embryos with EJMCh-6 was correlated with significantly increased embryo survival and a decrease in the bacterial burden as compared to those for untreated fish. Insights into the mechanism of action were inferred from the generation of spontaneous benzimidazole-resistant strains and the identification of a large set of missense mutations in MmpL3, the mycolic acid transporter in mycobacteria. Overexpression of the mutated mmpL3 alleles in a susceptible M. abscessus strain was associated with high resistance levels to EJMCh-6 and to other known MmpL3 inhibitors. Mapping the mutations conferring resistance on an MmpL3 three-dimensional homology model defined a potential EJMCh-6-binding cavity. These data emphasize a yet unexploited chemical structure class against M. abscessus with promising translational development for the treatment of M. abscessus lung diseases

Indoleamides are active against drug-resistant Mycobacterium tuberculosis

Responsible for nearly two million deaths each year, the infectious disease tuberculosis remains a serious global health challenge. The emergence of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis confounds control efforts, and new drugs with novel molecular targets are desperately needed. Here we describe lead compounds, the indoleamides, with potent activity against both drug-susceptible and drug-resistant strains of M. tuberculosis by targeting the mycolic acid transporter MmpL3. We identify a single mutation in mmpL3, which confers high resistance to the indoleamide class while remaining susceptible to currently used first- and second-line tuberculosis drugs, indicating a lack of cross-resistance. Importantly, an indoleamide derivative exhibits dose-dependent antimycobacterial activity when orally administered to M. tuberculosis-infected mice. The bioavailability of the indoleamides, combined with their ability to kill tubercle bacilli, indicates great potential for translational developments of this structure class for the treatment of drug-resistant tuberculosis