bm-212 and Tuberculosis

Tuberculosis (TB) continues to claim the lives of around 1.7 million people per year. Most concerning are the reports of multidrug drug resistance. Paradoxically, this global health pandemic is demanding new therapies when resources and interest are waning. However, continued tuberculosis drug discovery is critical to address the global health need and burgeoning multidrug resistance. Many diverse classes of antitubercular compounds have been identified with activity in vitro and in vivo. Our analyses of over 100 active leads are representative of thousands of active compounds generated over the past decade, suggests that they come from few chemical classes or natural product sources. We are therefore repeatedly identifying compounds that are similar to those that preceded them. Our molecule-centered cheminformatics analyses point to the need to dramatically increase the diversity of chemical libraries tested and get outside of the historic

Topics: Antitubercular Agents; Bacterial Proteins; Drug Discovery; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Nitroimidazoles; Nucleoside-Phosphate Kinase; Structure-Activity Relationship; Tuberculosis

1,5-Diphenyl pyrroles were previously identified as a class of compounds endowed with high in vitro efficacy against M. tuberculosis. To improve the physical chemical properties and drug-like parameters of this class of compounds, a medicinal chemistry effort was undertaken. By selecting the optimal substitution patterns for the phenyl rings at N1 and C5 and by replacing the thiomorpholine moiety with a morpholine one, a new series of compounds was produced. The replacement of the sulfur with oxygen gave compounds with lower lipophilicity and improved in vitro microsomal stability. Moreover, since the parent compound of this family has been shown to target MmpL3, mycobacterial mutants resistant to two compounds have been isolated and characterized by sequencing the mmpL3 gene; all the mutants showed point mutations in this gene. The best compound identified to date was progressed to dose-response studies in an acute murine TB infection model. The resulting ED(99) of 49 mg/Kg is within the range of commonly employed tuberculosis drugs, demonstrating the potential of this chemical series. The in vitro and in vivo target validation evidence presented here adds further weight to MmpL3 as a druggable target of interest for anti-tubercular drug discovery.

Topics: Animals; Antibiotics, Antitubercular; Bacterial Proteins; Cell Line; Female; Humans; Mice; Microbial Sensitivity Tests; Microsomes; Mycobacterium tuberculosis; Piperazines; Pyrroles; Tuberculosis

During the search of novel antitubercular drugs related to BM 212, new diarylpyrroles were designed and synthesized on the basis of a structure-activity relationship analysis of many pyrroles previously described by us. Among them, 1-(4-fluorophenyl)-2-ethyl-3-(thiomorpholin-4-yl)methyl-5-(4-methylphenyl)-1H-pyrrole (2b) proved to be particularly active, with a minimum inhibitory concentration (MIC, expressed as microg/mL) and a protection index (PI) better than or comparable to those of reference compounds. Also the remaining compounds were very active, although their MIC and PI were in general lower than those of their parent 2-methyl analogues.

Topics: Animals; Antitubercular Agents; Chlorocebus aethiops; Models, Molecular; Mycobacterium tuberculosis; Pyrroles; Quantitative Structure-Activity Relationship; Tuberculosis; Vero Cells