Molecular structure and vibrational spectroscopic studies of prothionamide by density functional theory.

Prothionamide (PTH) is the secondary drug used against Mycobacterium tuberculosis bacteria and leprosy. The aim of this work was to investigate the potential energy surface map, anharmonic and harmonic vibrational spectra, NBO analysis and ELF (Electron Localization Function) of the title compound using DFT approach with the B3LYP (Becke, three-parameter, Lee-Yang-Parr) exchange-correlation functional with the 6-31G++(d,p) and the Z3POLX basis sets were employed. In the experimental part of this study, FT-Mid IR, FT-Far IR and FT-Raman spectra of the molecule were recorded in the regions 4000-450cm(-1), 700-30cm(-1) and 4000-100cm(-1) respectively in the solid phase. The comparison between calculated and experimental vibrational spectra (infrared and Raman spectra) and assignments of fundamental vibrational modes were characterized by total energy distribution (TED). Theoretical spectra were seen to be in good agreement with those of the experimental ones.

Mechanism of thioamide drug action against tuberculosis and leprosy.

Thioamide drugs, ethionamide (ETH) and prothionamide (PTH), are clinically effective in the treatment of Mycobacterium tuberculosis, M. leprae, and M. avium complex infections. Although generally considered second-line drugs for tuberculosis, their use has increased considerably as the number of multidrug resistant and extensively drug resistant tuberculosis cases continues to rise. Despite the widespread use of thioamide drugs to treat tuberculosis and leprosy, their precise mechanisms of action remain unknown. Using a cell-based activation method, we now have definitive evidence that both thioamides form covalent adducts with nicotinamide adenine dinucleotide (NAD) and that these adducts are tight-binding inhibitors of M. tuberculosis and M. leprae InhA. The crystal structures of the inhibited M. leprae and M. tuberculosis InhA complexes provide the molecular details of target-drug interactions. The purified ETH-NAD and PTH-NAD adducts both showed nanomolar Kis against M. tuberculosis and M. leprae InhA. Knowledge of the precise structures and mechanisms of action of these drugs provides insights into designing new drugs that can overcome drug resistance.