Biological properties and conformational studies of amphiphilic Pd(II) and Ni(II) complexes bearing functionalized aroylaminocarbo-N-thioylpyrrolinate units

A series of novel palladium(II) and nickel(II) complexes of multifunctionalized aroylaminocarbo-N-thioylpyrrolinates were synthesized and characterized by analytical and spectroscopic techniques. The biological properties of the freshly prepared compounds were screened against S. aureus, B. subtilis, A. hydrophila, E. coli, and A. baumannii bacteria and antituberculosis activity against M. tuberculosis H37Rv strains. Also, the antifungal activity was studied against C. albicans, C. tropicalis, and C. glabrata standard strains. A deep conformational survey was monitored using DFT calculations with the aim to explain the importance of the final conformation in the biological experimental results.

Structure of mycobacterial CIII2CIV2 respiratory supercomplex bound to the tuberculosis drug candidate telacebec (Q203)

The imidazopyridine telacebec, also known as Q203, is one of only a few new classes of compounds in more than fifty years with demonstrated antituberculosis activity in humans. Telacebec inhibits the mycobacterial respiratory supercomplex composed of complexes III and IV (CIII2CIV2). In mycobacterial electron transport chains, CIII2CIV2 replaces canonical CIII and CIV, transferring electrons from the intermediate carrier menaquinol to the final acceptor, molecular oxygen, while simultaneously transferring protons across the inner membrane to power ATP synthesis. We show that telacebec inhibits the menaquinol:oxygen oxidoreductase activity of purified Mycobacterium smegmatis CIII2CIV2 at concentrations similar to those needed to inhibit electron transfer in mycobacterial membranes and Mycobacterium tuberculosis growth in culture. We then used electron cryomicroscopy (cryoEM) to determine structures of CIII2CIV2 both in the presence and absence of telacebec. The structures suggest that telacebec prevents menaquinol oxidation by blocking two different menaquinol binding modes to prevent CIII2CIV2 activity.

ABIETANE QUINONE DITERPENES WITH ANTITUBERCULOSIS ACTIVITY ISOLATED FROM THE GENUS SALVIA

The name Salvia, the largest genus of Lamiaceae, derives from the Latin "salvere" (= to feel good, healthy). In the Mediterranean basin, S. officinalis has been used since the time of the ancient Egyptians for medicinal purposes. Pliny the Elder was the first known author to describe a plant called "Salvia" by the Romans. Recent scientific research has confirmed the antituberculosis properties of numerous species present in the traditional ethnobotany.

Structure of mycobacterial CIII2CIV2 respiratory supercomplex bound to the tuberculosis drug candidate telacebec (Q203)

The imidazopyridine telacebec, also known as Q203, is one of only a few new classes of compound in more than fifty years with demonstrated antituberculosis activity in humans. Telacebec inhibits the mycobacterial respiratory supercomplex CIII2CIV2. In mycobacterial electron transport chains, CIII2CIV2 replaces canonical Complexes III and IV, transferring electrons from the intermediate carrier menaquinol to the final acceptor, molecular oxygen, while simultaneously pumping protons across the inner membrane to power ATP synthesis. We show that telacebec inhibits the menaquinol:oxygen oxidoreducase activity of purified Mycobacterium smegmatis CIII-2CIV2 at concentrations similar to those needed to inhibit electron transfer in mycobacterial membranes and Mycobacterium tuberculosis growth in culture. We then used electron cryomicroscopy (cryoEM) to determine structures of CIII2CIV2 both in the presence and absence of telacebec. The structures suggest that telacebec prevents menaquinol oxidation by blocking two different menaquinol binding modes to prevent CIII2CIV2 activity.

N-(Chlorobenzyl) Formamide as an Antituberculosis Agent from Multicomponent Reaction Synthesis

Tuberculosis (TB) is an infectious disease caused by M. tuberculosis. A new series of four benzylformamide with chloro substitution were synthesized by multicomponent reaction method and screened for antituberculosis activity against Mycobacterium tuberculosis H37Rv strain. This study was based on amidoalkylation reaction of aromatic-aldehyde, formamide and formic acid at 150oC to give a good yield of benzylformamide. Target compound were isolated, purificated, identified and characterized by GC-MS, FTIR, 1H-NMR, and 13C-NMR then the antituberculosis activity was examined by Microplate Alamar Blue Assay (MABA) and Middlebrook 7H9-7H11 medium in concentration series of 1000 – 1,954 μg/mL, and isoniazid as a positive control. Among the three derivative, N-(2,4-dichlorobenzyl) formamide has the most potential antituberculosis activity up to 500.0 L/mL.