Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide1, 2. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis3, 4, 5, several of which are currently in clinical trials6, 7, 8. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis

Trivalent copper and indium heterometallic complex with dithiocarbamate and iodide ligands

The heterometallic Cu???In complex salt [Cu(III) (dtc)2][In(III)I4](1) (dtc = S2CNEt2, diethyldithiocarbamate) was prepared by reactions of Cu(II) (dtc)2 and In(III)I3 in benzene solution. As a redox reaction, Cu(II) (dtc)2 was oxidized to [Cu(III) (dtc)2]+, and In(III)I3 was changed to [In(III)I4]???. The square???planar Cu(III)S4 local symmetry of 1 involves a distorted octahedral coordination environment via long???range intermolecular interactions and represents a new one-dimensional structure of [Cu(III) (dtc)2]+ units. The crystal packing system of 1 consists of many [Cu(III) (dtc)2]+ chains surrounded by six parallel chains without solvent molecules. The infrared spectra of 1 showed a higher-frequency C???N thioureide bond in Cu(III) (dtc)2 than that of pristine Cu(II) (dtc)2, which has a lower oxidation state due to the Cu(II) center

Chemoselective Trifluoroethylation Reactions of Quinazolinones and Identification of Photostability

Herein, we report chemoselective trifluoroethylation routes of unmasked 2-arylquinazolin-4(3H)-ones using mesityl(2,2,2-trifluoroethyl)iodonium triflate at room temperature. Homologous C-, O-, and N-functionalized subclasses are accessed in a straightforward manner with a wide substrate scope. These chemoselective branching events are driven by Pd-catalyzed ortho-selective C???H activation at the pendant aryl ring and base-promoted reactivity modulation of the amide group, leveraging the intrinsic directing capability and competing pronucleophilicity of the quinazolin-4(3H)-one framework. Furthermore, outstanding photostability of the quinazolin-4(3H)-one family associated with nonradiative decay is presented