Corrigendum to “Novel, potent, orally bioavailable and selective mycobacterial ATP synthase inhibitors that demonstrated activity against both replicating and non-replicating M. tuberculosis” [Bioorg. Med. Chem. 23 (2015) 742–752] (original) (raw)
Related papers
Bioorganic & Medicinal Chemistry, 2015
The mycobacterial F 0 F 1-ATP synthase (ATPase) is a validated target for the development of tuberculosis (TB) therapeutics. Therefore, a series of eighteen novel compounds has been designed, synthesized and evaluated against Mycobacterium smegmatis ATPase. The observed ATPase inhibitory activities (IC 50) of these compounds range between 0.36 and 5.45 lM. The lead compound 9d [N-(7-chloro-2-methylquinolin-4-yl)-N-(3-((diethylamino)methyl)-4-hydroxyphenyl)-2,3-dichlorobenzenesulfonamide] with null cytotoxicity (CC 50 >300 lg/mL) and excellent anti-mycobacterial activity and selectivity (mycobacterium ATPase IC 50 = 0.51 lM, mammalian ATPase IC 50 >100 lM, and selectivity >200) exhibited a complete growth inhibition of replicating Mycobacterium tuberculosis H37Rv at 3.12 lg/mL. In addition, it also exhibited bactericidal effect (approximately 2.4 log 10 reductions in CFU) in the hypoxic culture of nonreplicating M. tuberculosis at 100 lg/mL (32-fold of its MIC) as compared to positive control isoniazid [approximately 0.2 log 10 reduction in CFU at 5 lg/mL (50-fold of its MIC)]. The pharmacokinetics of 9d after p.o. and IV administration in male Sprague-Dawley rats indicated its quick absorption, distribution and slow elimination. It exhibited a high volume of distribution (V ss , 0.41 L/kg), moderate clearance (0.06 L/h/kg), long half-life (4.2 h) and low absolute bioavailability (1.72%). In the murine model system of chronic TB, 9d showed 2.12 log 10 reductions in CFU in both lung and spleen at 173 lmol/kg dose as compared to the growth of untreated control group of Balb/C male mice infected with replicating M. tuberculosis H37Rv. The in vivo efficacy of 9d is at least double of the control drug ethambutol. These results suggest 9d as a promising candidate molecule for further preclinical evaluation against resistant TB strains.
International Journal of Biological Macromolecules, 2019
The shortcomings of conventional tuberculosis treatments resulting from the development of drug resistance in Mycobacterium tuberculosis drive a need for the formulation of novel therapeutic agents. The diarylquinoline class of drugs such as bedaquiline was recently approved for the treatment of multidrug-resistant strains of tuberculosis, primarily targeting c and ε subunits of the ATP synthases. Yet resistance to bedaquiline has already been reported. Therefore, Rv1311 was used as the target for the identification of possible inhibitors against the M. tuberculosis. The structure of Rv1311 was predicted and common feature pharmacophore models were generated which facilitated the identification of potential inhibitors in the ZINC database. The activities of the selected molecules were compared with known inhibitors of the ATP synthase using quantitative structureactivity relationship. The ZINC classified inhibitors showed comparable predicted activities with that of known inhibitors. Furthermore, the inhibitory behavior of the studied drug molecules was experimentally determined using in vitro techniques and showed the minimum inhibitory concentration as low as 25 μM. The resulted outcomes provide a deeper insight into the structural basis of Rv1311 inhibitions and can facilitate the process of drug design against tuberculosis.
Acs chemical biology chand paper
Aminopyrazinamides originated from a high throughput screen targeting the Mycobacterium smegmatis (Msm) GyrB ATPase. This series displays chemical tractability, robust structure−activity relationship, and potent antitubercular activity. The crystal structure of Msm GyrB in complex with one of the aminopyrazinamides revealed promising attributes of specificity against other broad spectrum pathogens and selectivity against eukaryotic kinases due to novel interactions at hydrophobic pocket, unlike other known GyrB inhibitors. The aminopyrazinamides display excellent mycobacterial kill under in vitro, intracellular, and hypoxic conditions.
New J. Chem., 2015, 39, 7309--7321.pdf
A new, phenoxo-bridged Cu II dinuclear complex Cu 2 [(L) 2 (DMF) 2 ] (1) has been obtained by employing the coumarin-assisted tridentate precursor, H 2 L, [benzoic acid(7-hydroxy-4-methyl-2-oxo-2H-chromen-8ylmethylene)-hydrazide]. Complex 1 has been systematically characterized by FTIR, UV-Vis, fluorescence and EPR spectrometry. The single crystal X-ray diffraction analysis of 1 shows that the geometry around each copper ion is square pyramidal, comprising two enolato oxygen atoms belonging to different ligands (which assemble the dimer bridging the two metal centers), one imine-N and one phenolic-O atoms of the Schiff base and one oxygen atom from the DMF molecule. The temperature dependent magnetic interpretation agrees with the existence of weak ferromagnetic interactions between the bridging dinuclear Cu(II) ions. Both the ligand and complex 1 exhibit anti-mycobacterial activity and considerable efficacy towards M. tuberculosis H37Rv ATCC 27294 and M. tuberculosis H37Ra ATCC 25177 strains. The cytotoxicity study on human adenocarcinoma cell lines (MCF7) suggests that the ligand and complex 1 have potential anticancer properties. Molecular docking of H 2 L with the enoyl acyl carrier protein reductase of M. tuberculosis H37R v (PDB ID: 4U0K) is examined and the best docked pose of H 2 L shows one hydrogen bond with Thr196 (1.99 Å).
Novel chemotherapeutics agents are needed to kill Mycobacterium tuberculosis, the main causative agent of tuberculosis (TB). The M. tuberculosis 2-trans-enoyl-ACP(CoA) reductase enzyme (MtInhA) is the druggable bona fide target of isoniazid. New chemotypes were previously identified by two in silico approaches as potential ligands to MtInhA. The inhibition mode was determined by steady-state kinetics for seven compounds that inhibited MtInhA activity. Dissociation constant values at different temperatures were determined by protein fluorescence spectroscopy. van't Hoff analyses of ligand binding to MtInhA:NADH provided the thermodynamic signatures of non-covalent interactions (ΔH°, ΔS°, ΔG°). Phenotypic screening showed that five compounds inhibited in vitro growth of M. tuberculosis H37Rv strain. Labio_16 and Labio_17 compounds also inhibited the in vitro growth of PE-003 multidrug-resistant strain. Cytotoxic effects on Hacat, Vero and RAW 264.7 cell lines were assessed for the latter two compounds. The Labio_16 was bacteriostatic and Labio_17 bactericidal in an M. tuberculosis-infected macrophage model. In Zebrafish model, Labio_16 showed no cardiotoxicity whereas Labio_17 showed dose-dependent cardiotoxicity. Accordingly, a model was built for the MtInhA:NADH:Labio_16 ternary complex. The results show that the Labio_16 compound is a direct inhibitor of MtInhA, and it may represent a hit for the development of chemotherapeutic agents to treat TB. Tuberculosis (TB), caused mainly by Mycobacterium tuberculosis, still is one of the major threats in public health worldwide. In 2014, approximately 9.6 million people contracted TB, and the death toll was estimated as 1.5 million 1. In addition, an estimated 320,000 of new cases were multidrug-resistant TB (MDR-TB) claiming the lives of 190,000 people, and 9.7% of resistant TB are extensively drug-resistant (XDR-TB) 1. Drug resistance severely threatens TB control, by increasing the probability of a return to a time when drugs are no longer effective 2 .
Bioorganic & Medicinal Chemistry, 2013
The alarming increase in bacterial resistance over the last decade along with a dramatic decrease in new treatments for infections has led to problems in the healthcare industry. Tuberculosis (TB) is caused mainly by Mycobacterium tuberculosis which is responsible for 1.4 million deaths per year. A worldwide threat with HIV co-infected with multi and extensively drug-resistant strains of TB has emerged. In this regard, herein, novel acrylic acid ethyl ester derivatives were synthesized in simple, efficient routes and evaluated as potential agents against several Mycobacterium species. These were synthesized via a stereospecific process for structure activity relationship (SAR) studies. Minimum inhibitory concentration (MIC) assays indicated that esters 12, 13, and 20 exhibited greater in vitro activity against Mycobacterium smegmatis than rifampin, one of the current, first-line anti-mycobacterial chemotherapeutic agents. Based on these studies the acrylic ester 20 has been developed as a potential lead compound which was found to have an MIC value of 0.4 μg/mL against Mycobacterium tuberculosis. The SAR and biological activity of this series is presented; a Michael-acceptor mechanism appears to be important for potent activity of this series of analogs.
Journal of Molecular Structure 1139 (2017) 137-
Series of ferrocenyl substituted chromophores were synthesized via a reaction of acetyl ferrocene and a variety of aldehyde under microwave irradiation. The structure of synthesized compounds were established by spectroscopic (FT-IR, 1 H NMR, 13 C NMR, ESI-MS) and elemental analysis. UVeVis and fluorescence spectroscopy measurements provided that all compounds have good absorbent and fluorescent properties. Fluorescence polarity studies demonstrated that these compounds were sensitive to the polarity of the microenvironment provided by different solvents. In addition, spectroscopic and physicochemical parameters, including singlet absorption, extinction coefficient, Stokes shift, oscillator strength and dipole moment, were investigated in order to explore the analytical potential of the synthesized compounds. The anti-bacterial activity of these compounds were first studied in vitro by the disk diffusion assay against two Gram-positive and two Gram-negative bacteria. The minimum inhibitory concentration was then determined with the reference of standard drug chloramphenicol. The results displayed that compound 3 was better inhibitors for both types of the bacteria (Gram-positive and Gramnegative) than chloramphenicol. Based on the density functional theory; total energy, the atomic orbital contribution to frontier orbitals: LUMO and HOMO, of all synthesized compounds were calculated to support the antibacterial activities.
Inorg. Chem. Front., 2015,.pdf
A potential tetradentate monoanionic N 2 O 2 chelator, HL, derived from the condensation of o-vanillin and N,N-dimethylethylenediammine, has been reacted with nickel perchlorate and sodium azide to yield the dinuclear Ni(II) complex [Ni(L)(μ 1,1 -N 3 )Ni(L)(OH 2 ) 2 ]·ClO 4 (1), where L = Me 2 N(CH 2 ) 2 NvCH-C 6 H 3 (O − )-(OCH 3 ). The complex has been characterized by X-ray diffraction analysis and different spectroscopic techniques. The coordination geometry around the Ni(II) centres is a distorted octahedron, with the azide ligand and the phenolato oxygen atom bridging in μ 1,1 and μ 2 mode, respectively. The EPR spectra, recorded at liquid nitrogen temperature (77 K) and room temperature ), show g factors of 2.080 and 2.085, in agreement with the structure determined by X-ray diffraction analysis. The VTM study confirms that there are ferromagnetic interactions between the bridging binuclear Ni(II) ions (S = 1). The evaluation of cytotoxic effects on different human cancer cell lines (A-549, MCF-7 and CaCo-2) suggests that both the ligand and complex 1 have potential anticancer properties. Furthermore, they also exhibit anti-mycobacterial activity against M. tuberculosis H37Rv (ATCC 27294) and M. tuberculosis H37Ra (ATCC 25177) strains. Molecular docking of HL with the enoyl acyl carrier protein reductase of M. tuberculosis H37R v (PDB ID: 4U0K) has been examined, showing that HL forms two hydrogen bonds with Lys165 (1.94 and 2.53 Å) in its best docked pose. † Electronic supplementary information (ESI) available. CCDC 894363. For ESI and crystallographic data in CIF or other electronic format see