Synthesis and biological evaluation of 3,4-dihydro-1H-[1,4] oxazepino [6,5,4-hi] indol-1-ones and 4,6-dihydrooxepino [5,4,3-cd] indol-1(3H)-ones as Mycobacterium tuberculosis inhibitors.

This study focuses on the synthesis of 1,7- and 3,4-indole-fused lactones via a simple and efficient reaction sequence. The functionalization of these "oxazepino-indole" and "oxepino-indole" tricycles is carried out by palladium catalysed CC coupling, nucleophilic substitution or 1,3-dipolar cycloaddition. The evaluation of their activity against Mycobacterium tuberculosis shows that the "oxazepino-indole" structure is a new inhibitor of M.

Biological and Biochemical Evaluation of Isatin-Isoniazid Hybrids as Bactericidal Candidates against .

Tuberculosis remains a leading cause of mortality among infectious diseases worldwide, prompting the need to discover new drugs to fight this disease. We report here the design, synthesis, and antimycobacterial activity of isatin-mono/bis-isoniazid hybrids. Most of the compounds exhibited very high activity against Mycobacterium tuberculosis, with MICs in the range of 0.

Rifabutin Is Bactericidal against Intracellular and Extracellular Forms of Mycobacterium abscessus.

is increasingly recognized as an emerging opportunistic pathogen causing severe lung diseases. As it is intrinsically resistant to most conventional antibiotics, there is an unmet medical need for effective treatments. Repurposing of clinically validated pharmaceuticals represents an attractive option for the development of chemotherapeutic alternatives against infections.

Synthesis and evaluation of heterocycle structures as potential inhibitors of Mycobacterium tuberculosis UGM.

In this study, we screen three heterocyclic structures as potential inhibitors of UDP-galactopyranose mutase (UGM), an enzyme involved in the biosynthesis of the cell wall of Mycobacterium tuberculosis. In order to understand the binding mode, docking simulations are performed on the best inhibitors. Their activity on Mycobacterium tuberculosis is also evaluated.

Efficacy of Bedaquiline, Alone or in Combination with Imipenem, against Mycobacterium abscessus in C3HeB/FeJ Mice.

lung infections remain difficult to treat. Recent studies have recognized the power of new combinations of antibiotics, such as bedaquiline and imipenem, although data have questioned this combination. We report that the efficacy of bedaquiline-imipenem combination treatment relies essentially on the activity of bedaquiline in a C3HeB/FeJ mice model of infection with a rough variant of The addition of imipenem contributed to clearing the infection in the spleen.

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

New drugs or therapeutic combinations are urgently needed against Previously, we demonstrated the potent activity of indole-2-carboxamides 6 and 12 against We show here that these compounds act synergistically with imipenem and cefoxitin and increase the bactericidal activity of the β-lactams against 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.

Active Benzimidazole Derivatives Targeting the MmpL3 Transporter in .

The prevalence of pulmonary infections due to nontuberculous mycobacteria such as 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- therapeutics are urgently needed against this emerging pathogen. Extensive screening of a library of benzimidazole derivatives that were previously shown to be active against led to the identification of a lead compound exhibiting very potent in vitro activity against a wide panel of clinical strains.

Verapamil Improves the Activity of Bedaquiline against Mycobacterium abscessus In Vitro and in Macrophages.

Due to intrinsic multidrug resistance, pulmonary infections with are extremely difficult to treat. Previously, we demonstrated that bedaquiline is highly effective against both and Here, we report that verapamil improves the efficacy of bedaquiline activity against clinical isolates and low-level resistant strains, both and in macrophages. Verapamil may have clinical potential as adjunctive therapy provided that sufficiently high doses can be safely achieved.