Azaindoles: Noncovalent DprE1 Inhibitors from Scaffold Morphing Efforts, Kill Mycobacterium tuberculosis and Are Efficacious in Vivo (original) (raw)
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1,4-azaindole, a potential drug candidate for treatment of tuberculosis
Antimicrobial agents and chemotherapy, 2014
New therapeutic strategies against multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis are urgently required to combat the global tuberculosis (TB) threat. Toward this end, we previously reported the identification of 1,4-azaindoles, a promising class of compounds with potent antitubercular activity through noncovalent inhibition of decaprenylphosphoryl-β-D-ribose…
Journal of Molecular Graphics and Modelling, 2020
Cell wall of mycobacterium acts as a primary interface which helps in the regulation of important functions and also aids to pathogenicity and virulence of the organism, making it a crucial target for drug discovery. Decaprenylphosphoryl-D-ribose 2 0-epimerase (DprE), is important for the growth and survival of Mycobacterium tuberculosis. DprE1 is a donor of arabinose sugars which helps in the formation of cell wall components-lipoarabinomannan and arabinogalactan through Decaprenyl-phosphoryl D-arabinose (DPA) pathway. In our study, we have chosen Azaindole derivatives as DprE1 inhibitors which possess non-covalent property. TBA7371 (azaindole derivative, non-covalent inhibitor) is currently in first phase of clinical trials as DprE1 inhibitor. Azaindoles have been found to be equally potent against drugsensitive and isoniazid/rifampin-resistant strains. Hence, azaindoles are an attractive class for further optimization as potential DprE1 inhibitors for TB. Structure-based pharmacophore model was generated to investigate the compounds with similar molecular features. Compounds having a good fitness score and pharmacophoric features were compared with the molecules in clinical trial and were proceeded for molecular docking studies to identify the binding affinity of the compounds with target protein DprE1. Energy based calculations using Prime MM-GBSA of Schrodinger was further executed to examine free binding energy of the ligands. The prediction of pharmacokinetic parameters (ADME) plays an important role to identify safe and potent molecules which may further have potential to become drug candidates. Induced-fit docking approach and Molecular Dynamics integrated with Prime MM-GBSA calculations of both hit compounds has further confirmed the binding affinity and stability. All the results obtained from our study were interpreted and compared with DprE1 inhibitor in clinical trials. Study identified ZINC000170252277 as a potential hit compound for further biological evaluation as DprE1 inhibitor.
Overview of the Development of DprE1 Inhibitors for Combating the Menace of Tuberculosis
Journal of medicinal chemistry, 2018
Decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1), a vital enzyme for cell wall synthesis, plays a crucial role in the formation of lipoarabinomannan and arabinogalactan. It was first reported as a druggable target on the basis of inhibitors discovered in high throughput screening of a drug library. Since then, inhibitors with different types of chemical scaffolds have been reported for their activity against this enzyme. Formation of a covalent or noncovalent bond by the interacting ligand with the enzyme causes loss of its catalytic activity which ultimately leads to the death of the mycobacterium. This Perspective describes various DprE1 inhibitors as anti-TB agents reported to date.
Chemistry Central Journal, 2018
Tuberculosis has proved harmful to the entire history of mankind from past several decades. Decaprenyl-phosphorylribose 2′-epimerase (DprE1) is a recent target which was identified in 2009 but unfortunately it is neither explored nor crossed phase II. In past several decades few targets were identified for effective antitubercular drug discovery. Resistance is the major problem for effective antitubercular drug discovery. Arabinose is constituent of mycobacterium cell wall. Biosynthesis of arabinose is FAD dependant two step epimerisation reaction which is catalysed by DprE1 and DprE2 flavoprotein enzymes. The current review is mainly emphases on DprE1 as a perspective challenge for further research.
Journal of Medicinal Chemistry, 2014
4-Aminoquinolone piperidine amides (AQs) were identified as a novel scaffold starting from a whole cell screen, with potent cidality on Mycobacterium tuberculosis (Mtb). Evaluation of the minimum inhibitory concentrations, followed by whole genome sequencing of mutants raised against AQs, identified decaprenylphosphoryl-β-D-ribose 2′-epimerase (DprE1) as the primary target responsible for the antitubercular activity. Mass spectrometry and enzyme kinetic studies indicated that AQs are noncovalent, reversible inhibitors of DprE1 with slow on rates and long residence times of ∼100 min on the enzyme. In general, AQs have excellent leadlike properties and good in vitro secondary pharmacology profile. Although the scaffold started off as a single active compound with moderate potency from the whole cell screen, structure−activity relationship optimization of the scaffold led to compounds with potent DprE1 inhibition (IC 50 < 10 nM) along with potent cellular activity (MIC = 60 nM) against Mtb.
Pharmaceutical Chemistry Journal
Emergence of various forms of resistant strains of Mycobacterium tuberculosis led to the exploration of drugs with novel mechanism of action. Recently econazole, an azole based antitubercular agent, attracted major attention for targeting mycobacterial cytochrome P450. In the present study, we designed novel 1,2,4-triazole derivatives based on econazole moiety and evaluated them for in vitro antitubercular activity against M. tuberculosis H37Rv and multi-drug resistant (MDR) strains of Mycobacterium.
Objective: RmlC (dTDP-6-deoxy-D-xylo-4-hexulose 3, 5-epimerase) is a crucial enzyme for cell wall biosynthesis in Mycobacterium tuberculosis. It's absence in human host attest it as a valid target for drug designing. In the presented study an in-silico method is employed to find out the potential phytochemical inhibitors of RmlC. Methods: AutoDock 4.2 is used to study the binding affinity of ligands in the active site of the protein. The drug-likeness and oral toxicity evaluation is done using the online tools Molsoft and ProTox respectively. Results: Chrysophanol has binding affinity of-9.24 kcal/mole to RmlC active site. PASS tool predicts chrysophanol as antitubercular compound. Its druglikeness is 0.1, and toxicity class is 5 measured by ProTox. Hence, chrysophanol emerges as a lead molecule among the phytochemicals in the database. Conclusions: Crysophanol is the lead inhibitor against RmlC target. The lead molecule may work as a successful drug in future for tuberculosis treatment.
Benzimidazoles: Novel Mycobacterial Gyrase Inhibitors from Scaffold Morphing
ACS Medicinal Chemistry Letters, 2014
Type II topoisomerases are well conserved across the bacterial species, and inhibition of DNA gyrase by fluoroquinolones has provided an attractive option for treatment of tuberculosis (TB). However, the emergence of fluoroquinolone-resistant strains of Mycobacterium tuberculosis (Mtb) poses a threat for its sustainability. A scaffold hopping approach using the binding mode of novel bacterial topoisomerase inhibitors (NBTIs) led to the identification of a novel class of benzimidazoles as DNA gyrase inhibitors with potent anti-TB activity. Docking of benzimidazoles to a NBTI bound crystal structure suggested that this class of compound makes key contacts in the enzyme active site similar to the reported NBTIs. This observation was further confirmed through the measurement of DNA gyrase inhibition, and activity against Mtb strains harboring mutations that confer resistance to aminopiperidines based NBTIs and Mtb strains resistant to moxifloxacin. Structure−activity relationship modification at the C-7 position of the left-hand side ring provided further avenue to improve hERG selectivity for this chemical series that has been the major challenges for NBTIs.
ACS Infectious Diseases
The phenoxy alkyl benzimidazoles (PABs) have good antitubercular activity. We expanded our structure− activity relationship studies to determine the core components of PABs required for activity. The most potent compounds had minimum inhibitory concentrations against Mycobacterium tuberculosis in the low nanomolar range with very little cytotoxicity against eukaryotic cells as well as activity against intracellular bacteria. We isolated resistant mutants against PAB compounds, which had mutations in either Rv1339, of unknown function, or qcrB, a component of the cytochrome bc 1 oxidase of the electron transport chain. QcrB mutant strains were resistant to all PAB compounds, whereas Rv1339 mutant strains were only resistant to a subset, suggesting that QcrB is the target. The discovery of the target for PAB compounds will allow for the improved design of novel compounds to target intracellular M. tuberculosis.
Bioorganic & medicinal …, 2009
A series of novel enantiomerically pure azole derivatives was synthesized. The new compounds, bearing both an imidazole as well as a triazole moiety, were evaluated as antimycobacterial agents. One of them proved to have activity against Mycobaterium tuberculosis comparable to those of the classical antibacterial/antifungal drugs Econazole and Clotrimazole. Tuberculosis (TB) is a common and deadly infectious disease caused by mycobacteria, mainly Mycobacterium tuberculosis. Over one-third of the world's population has been exposed to the TB bacterium, and new infections occur at a rate of one per second. 1 In 2005, mortality and morbidity statistics included 14.6 million chronic active TB cases, 8.9 million new cases, and 1.6 million deaths, mostly in developing countries. 2 In addition, the rising number of people who are contracting TB because of their immune systems compromised by immunosuppressive drugs or substance abuse or HIV/AIDS, is a serious threat to TB control and prevention. Moreover the emergence of multi-drug resistance TB (MDR-TB), defined as resistance to at least isoniazid and rifampin, and the extensively drug resistant (XDR-TB) strains make the discovery and the development of new drugs a priority. 3 In the last few years, the determination of the genome sequence of Mycobacterium tuberculosis 4,5 (MTB) provided a much needed boost for research into new drug targets against this pathogen. In particular, recent promising data suggest that targeting the lipid metabolism pathways of MTB may provide an excellent route to attenuating or killing the bacterium. The genome of MTB encodes for a relatively large number of cytochrome P450 enzymes. These data indicate important physiological roles for these enzymes which, given that the substrate preference of the majority of P450s is for hydrophobic molecules, most are likely to be involved in lipid metabolism. McLean and co-workers cloned and expressed MTB CYP51 and CYP121, two types of P450 from MTB. 6 They demonstrated that CYP51 and CYP121 bind azole antifungal drugs tightly and that azole compounds are potent inhibitor of cell growth of Mycobacterium bovis and Mycobacterium smegmatis, two mycobacterial species which closely resemble MTB. Azole drugs proved to have also antitubercular activities in mice. 7 Finally, recent studies furnished the crystal structure of MTB cytochrome P450 CYP121 in complex with the fluconazole. 8 It has been found that MTB-CYP121 binds commercially available azole drugs as clotrimazole or econazole and that it may be the true target for the antimycobacterial activity of the azoles in vivo as suggested by gene-knockout studies. In this context, as a continuation of our previous works on the discovery of new antimicrobial agents, 11,12 we decided to focus our attention on the synthesis and preliminary biological evaluation against MTB of novel azole analogues with polycyclic structure A which resemble the classical antifungal/antibacterial azole drugs . Being the target compounds chiral, we were also attracted by the possibility of synthesizing these derivatives in enantiomerically pure form in order to evaluate the biological profile of the single enantiomers.