Identification of a small molecule with activity against drug-resistant and persistent tuberculosis

A cell-based phenotypic screen for inhibitors of biofilm formation in mycobacteria identified the small molecule TCA1, which has bactericidal activity against both drug-susceptible and -resistant Mycobacterium tuberculosis (Mtb) and sterilizes Mtb in vitro combined with rifampicin or isoniazid. In addition, TCA1 has bactericidal activity against nonreplicating Mtb in vitro and is efficacious in acute and chronic Mtb infection mouse models both alone and combined with rifampicin or isoniazid. Transcriptional analysis revealed that TCA1 down-regulates genes known to be involved in Mtb persistence. Genetic and affinity-based methods identified decaprenyl-phosphoryl-beta-D-ribofuranose oxidoreductase DprE1 and MoeW, enzymes involved in cell wall and molybdenum cofactor biosynthesis, respectively, as targets responsible for the activity of TCA1. These in vitro and in vivo results indicate that this compound functions by a unique mechanism and suggest that TCA1 may lead to the development of a class of antituberculosis agents

A novel pyrazolopyridine with in vivo activity in Plasmodium berghei- and Plasmodium falciparum-infected mouse models from structure-activity relationship studies around the core of recently identified antimalarial imidazopyridazines

Toward improving pharmacokinetics, in vivo efficacy, and selectivity over hERG, structure-activity relationship studies around the central core of antimalarial imidazopyridazines were conducted. This study led to the identification of potent pyrazolopyridines, which showed good in vivo efficacy and pharmacokinetics profiles. The lead compounds also proved to be very potent in the parasite liver and gametocyte stages, which makes them of high interest

Hit-to-Lead Studies for the Antimalarial Tetrahydroisoquinolone Carboxanilides

Phenotypic whole-cell screening in erythrocytic cocultures of <i>Plasmodium falciparum</i> identified a series of dihydroisoquinolones that possessed potent antimalarial activity against multiple resistant strains of <i>P. falciparum in vitro</i> and show no cytotoxicity to mammalian cells. Systematic structure–activity studies revealed relationships between potency and modifications at N-2, C-3, and C-4. Careful structure–property relationship studies, coupled with studies of metabolism, addressed the poor aqueous solubility and metabolic vulnerability, as well as potential toxicological effects, inherent in the more potent primary screening hits such as <b>10b</b>. Analogues <b>13h</b> and <b>13i</b>, with structural modifications at each site, were shown to possess excellent antimalarial activity <i>in vivo</i>. The (+)-(3<i>S</i>,4<i>S</i>) enantiomer of <b>13i</b> and similar analogues were identified as the more potent. On the basis of these studies, we have selected (+)-<b>13i</b> for further study as a preclinical candidate