Anti-tuberculosis Candidates Research Articles

Safety, pharmacokinetics, and food effect of sudapyridine (WX-081), a novel anti-tuberculosis candidate in healthy Chinese subjects.

This study aimed to assess the safety, pharmacokinetics, and food impact on sudapyridine (WX-081), a novel drug designed to inhibit mycobacterium ATP synthase, with clinical applications for drug-resistant tuberculosis (TB) treatment. The research comprised two arms: a single ascending dose (SAD) arm (30 to 600 mg, N = 52) and a multiple ascending dose (MAD) arm (200 to 400 mg, N = 30). The influence of food was evaluated using a 400 mg dose within an SAD cohort. Plasma concentrations of WX-081 and M3 (main metabolite of WX-081) were analyzed using a validated liquid-chromatography tandem mass spectrometry method. In the SAD arm, mean residence time (MRT0-t), terminal half-life, and clearance of WX-081 ranged from 18.87 to 52.8 h, 31.39 to 236.57 h, and 6.4 to 80.34 L/h, respectively. The area under the curve from time zero to the last measurable timepoint (AUC0-t) of WX-081 showed dose-proportional increases in the SAD arm. The disparity between fasted and fed states of WX-081 was significant (p < 0.05), with fed dosing resulting in a 984.07% higher AUC0-t and 961.55% higher maximum plasma concentration. In both the SAD and MAD arms, one case each exhibited a 1 degree atrioventricular block. No QTc elongation was observed, and adverse events were not dose-dependent. Favorable exposure, tolerability, safety, and an extended MRT0-t suggest that WX-081 holds promise as a phase II development candidate for drug-resistant TB treatment.

Evaluation of Acute and Sub-Acute Toxicity, Oxidative Stress and Molecular Docking of Two Nitrofuranyl Amides as Promising Anti-Tuberculosis Agents.

Tuberculosis (TB) remains a widespread infectious disease and one of the top 10 causes of death worldwide. Nevertheless, despite significant advances in the development of new drugs against tuberculosis, many therapies and preventive measures do not lead to the expected favorable health results for various reasons. The aim of this study was to evaluate the acute and sub-acute toxicity and oxidative stress of two selected nitrofuranyl amides with high in vitro antimycobacterial activity. In addition, molecular docking studies were performed on both compounds to elucidate the possibilities for further development of new anti-tuberculosis candidates with improved efficacy, selectivity, and pharmacological parameters. Acute toxicity tests showed that no changes were observed in the skin, coat, eyes, mucous membranes, secretions, and vegetative activity in mice. The histological findings include features consistent with normal histological architecture without being associated with concomitant pathological conditions. The observed oxidative stress markers indicated that the studied compounds disturbed the oxidative balance in the mouse liver. Based on the molecular docking, compound DO-190 showed preferable binding energies compared to DO-209 in three out of four targets, while both compounds showed promising protein-ligand interactions. Thus, both studied compounds displayed promising activity with low toxicity and can be considered for further evaluation and/or lead optimization.

Drug Repurposing for the Treatment of Mycobacterium abscessus Infections

Abstract With the ever-increasing burden of antimicrobial resistance, the demand to introduce countermeasures becomes increasingly critical. The urgency of this need is intensified by the void in antibiotic discovery, with the identification of novel compounds declining with time. Of increasing concern is Mycobacterium abscessus, which displays high levels of intrinsic resistance that lead to poor success rates, even after lengthy drug regimens. Research tackling these issues is now focused on the repurposing of preexisting drugs for antimycobacterial use, facilitating the discovery of antimicrobial compounds amidst a crisis where novel antibiotics are sparse. Part of this includes the use of combination treatments, whereby coadministration of synergistic compounds can reduce dose requirements and slow the progression of antimicrobial resistance in the long term. In this review, we will introduce the current therapeutic options for M. abscessus and provide insight into why treatment is so burdensome. We will also compile the current updates within drug repurposing for this pathogen, including the use of unconventional agents such as antimalarial drugs, the repositioning of antituberculosis candidates and the repurposing of preexisting antibiotics, including the application of combination regimens. In addition, the in vitro drug screening platforms used in their discovery will be appraised, with the view of highlighting potential future perspectives that may help increase physiological relevance. This review provides a timely appraisal of the future of M. abscessus treatment.

Mycobacterium tuberculosis DprE1 Inhibitor OPC-167832 Is Active against Mycobacterium abscessus In Vitro.

The antituberculosis candidate OPC-167832, an inhibitor of DprE1, was active against Mycobacterium abscessus. Resistance mapped to M. abscessus dprE1, suggesting target retention. OPC-167832 was bactericidal and did not antagonize activity of clinical anti-M. abscessus antibiotics. Due to its moderate potency compared to that against Mycobacterium tuberculosis, the compound lacked efficacy in a mouse model and is thus not a repurposing candidate. These results identify OPC-167832-DprE1 as a lead-target couple for a M. abscessus-specific optimization program.

Transition-metal-free, one-pot synthesis of benzoxaboroles from o-bromobenzaldehydes via visible-light-promoted borylation.

A novel and simple one-pot stepwise method to synthesize benzoxaboroles was demonstrated. This step-by-step synthetic method includes photocatalytic boronization with phenothiazine as a photocatalyst and sequential water-induced reduction in the presence of bis(pinacolato)diboron. A series of o-bromobenzaldehydes were well-tolerated under the standard conditions. In addition, this method has been successfully applied in the synthesis of the anti-tuberculosis candidate drug GSK 3036656 and anti-fungal drug tavaborole.

Synthesis, Characterization and In Silico Study of Fe(III) Complex with N'-(4-Chlorobenzoyl)-Isonicotino-Hydrazide as Anti Tuberculosis Candidate

The synthesis of Fe(III) complexes with ligands N'-(4-Chlorobenzoyl)isonicotinohydrazide can be synthesized through mixing metal and ligand dissolved in ethanol by reflux at ± 75oC for 5 hours. The instruments for the characterization of the complex were used UV-Visible and Infrared Spectrophotometry. The aims of the study are: to determine the synthesis method, characterize of the complex, and to study the interaction of the complex with target receptors. The weight of the synthesized compound was obtained by 38.1 mg. The purity of the complex has been tested using the determination of melting point and got a melting point range was 196-198oC. The maximum wavelength of Fe(III)N'-(4-Chlorobenzoyl)isonicotinohydrazid) complex was 261.0 nm and provide absorption of Fe-O vibrations at wavenumbers 530.42 cm-1. The docking process was done using AutodockTools-1.5.6 software which shows that the Fe(III)N'-(4-Chlorobenzoyl) isonicotinohydrazide complex can interact with Enoyl-Acyl Carrier Protein Reductase from Mycobacterium Tuberculosis and it has better interaction than isoniazid or N'-(4-Chlorobenzoyl)isonicotinohydrazide compound with the acquisition of free energy binding (ΔG) -9.80 kcal/mol and inhibition constant (Ki ) 0.06529 μM.

Development and validation of a sensitive LC-MS/MS method for the quantitation of IMB-YH-4py5-2H, an antituberculosis candidate, and its application to the pharmacokinetic study.

(E)-N,N-dimethyl-4-oxo-4-(4-(pyridin-4-yl)phenyl)but-2-enamide hydrochloride (IMB-YH-4py5-2H) is a novel Protein Kinase B (PknB) inhibitor with potent activity against Mycobacterium tuberculosis strains. In the present study, a sensitive and specific liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and validated to determine IMB-YH-4py5-2H in rat plasma. Sample pretreatment was achieved by liquid-liquid extraction with ethyl acetate, and separation was performed on an XTerra MS C18 column (2.1×50 mm, 3.5 μm) with gradient elution (methanol and 0.1% formic acid) at a flow rate of 0.3 mL/min. Detection was performed in multiple reaction monitoring (MRM) mode. Linear calibration curves were obtained over a concentration range of 1−100 ng/mL. The intra-day and inter-day precisions were lower than 8.46%, and the accuracies ranged from -8.71% to 12.36% at all quality control levels. The extraction recoveries were approximately 70%, and the matrix effects were negligible. All quality control samples were stable under different storage conditions. The validated method was successfully applied to a preclinical pharmacokinetic study in Sprague-Dawley rats. IMB-YH-4py5-2H demonstrated improved pharmacokinetic properties (higher exposure level) compared with its leading compound. IMB-YH-4py5-2H was also distributed throughout the lung pronouncedly, especially inside alveolar macrophages, indicating its effectiveness against lower respiratory infections.

Nonclinical evaluation of IQG-607, an anti-tuberculosis candidate with potential use in combination drug therapy

New effective compounds to treat tuberculosis are urgently needed. IQG-607 is an orally active anti-tuberculosis drug candidate, with promising preliminary safety profile and anti-mycobacterial activity in both in vitro and in vivo models of tuberculosis infection. Here, we evaluated the mutagenic and genotoxic effects of IQG-607, and its interactions with CYP450 isoforms. Moreover, we describe for the first time a combination study of IQG-607 in Mycobacterium tuberculosis-infected mice. Importantly, IQG-607 had additive effects when combined with the first-line anti-tuberculosis drugs rifampin and pyrazinamide in mice. IQG-607 presented weak to moderate inhibitory potential against CYP450 isoforms 3A4, 1A2, 2C9, 2C19, 2D6, and 2E1. The Salmonella mutagenicity test revealed that IQG-607 induced base pair substitution mutations in the strains TA100 and TA1535. However, in the presence of human metabolic S9 fraction, no mutagenic effect was detected in any strain. Additionally, IQG-607 did not increase micronucleus frequencies in mice, at any dose tested, 25, 100, or 250 mg/kg. The favorable activity in combination with first-line drugs and mild to moderate toxic events described in this study suggest that IQG-607 represents a candidate for clinical development.

Uji In Vitro dan Studi In Silico Senyawa Turunan n’-benzoylisonicotinohydr

Telah dilakukannya penelitian tentang studi in vitro dan in silico senyawa turunan N-Benzoylisonicotinohydrazide. Penelitian ini bertujuan untuk mengetahui bahwa senyawa turunan N’-benzoylisonicotinohydrazide dapat menghambat aktivitas bakteri gram positif, gram negatif dan Mycobacterium tuberculosis, serta mempunyai interaksi yang baik dengan Enoyl-Acyl Carrier Protein Reductase dari Mycobacterium Tuberculosis. Dari uji in vitro dihasilkan bahwa senyawa N’-benzoylisonicotinohydrazide memiliki Minimum Inhibitor Concentration (MIC) sebesar 0,33 µg/ml terhadap bakteri Basillus subtilis, sedangkan besarnya Minimum Inhibitor Concentration (MIC) senyawa N’-(2-chlorobenzoyl)isonicotinohydrazide terhadap Mycobacterium tuberkulosis (H37Rv) adalah sebesar 3,125 µg/ml. Dari studi in silico didapat bahwa nilai binding affinity antara senyawa N’-(2-chlorobenzoyl)isonicotinohydrazide enzim Enoyl-Acyl Carrier Protein Reductase (2X23) mempunyai binding affinity yang paling kecil sehingga dapat diprediksi bahwa senyawa tersebut mempunyai interaksi yang stabil dan paling baik disbanding senyawa-senyawa lainnya sehingga senyawa N’-(2-chlorobenzoyl)isonicotinohydrazide dapat digunakan sebagai kandidat antituberkulosis yang lebih poten.

The Biology Activities of Isonicotinohydrazide Derivatives as an Anti-tuberculosis Candidate

The compound N’-(3-chlorobenzoyl)isonicotinohydrazide, N’-(3-bromobenzoyl) isonicotinodyrazide, N’-(4-fluorobenzoyl)isonicotinohydrazide are isonicotinohydrazide derivative compounds which have antibacterial activity against bacteria Staphylococcus aureus, bacteria Bacillus subtilis as gram-positive Escherichia coli as gram-negative, and against strain Mycobacterium tuberculosis H37Rv. The purpose of this study was to obtain antituberculous candidates from isonicotinohydrazide compounds. The method used to test the antibacterial activity was the disc diffusion while for antimycobacterium using method Resazurin Microtiter Assay (REMA). The results of the antibacterial activity test on the bacteria Staphylococcus aureus compound N’-(3-chlorobenzoyl)isonicotinohydrazide had the lowest MIC value (0.26 ppm), while the bacteria Bacillus subtilis and Escherichia coli compound with the lowest MIC value of N’-(3-bromobenzoil)isonicotinodyrazide with a MIC value of 0.30 and 0,24 ppm. In the bacterium M. tuberculosis, H37Rv compound isoniazid has the smallest MIC value (3.125 ppm).

Synthesis and Characterization of Fe(III) Complex with N’- (3-Nitrobenzoyl)Isonicotinohydrazide as an Anti-tuberculosis Candidate

Recently, we have been conducted synthesis of complex compounds of Fe(III)N’-(3- nitrobenzoyl)isonicotinohydrazideusing refluxing N’-(3 -nitrobenzoyl)isonicotinohydrazideas ligands and FeCl3.6H2O as the metal at 75 °C for 6 hours in ethanol. The synthesis results obtained82.45% recovery, and from the purity test are shown with a narrow melting range is 220-222°C. Based on identification with UV-Visible spectrophotometer, infrared spectrometer and Atomic Absorption Spectrophotometer (AAS) indicate that the complex compound have λmax of 272.00 nm, giving vibration of Fe-O at 495.1 cm−1 and 599.6 cm−1 with formula complex compounds, namely [Fe(C13H10N4O4(H2O)4)Cl3].10 H2O.

Synthesis and molecular docking of isonicotinohydrazide derivatives as anti-tuberculosis candidates

Tuberculosis (TB) is a chronic disease as a result of Mycobacterium tuberculosis. It can affect all age groups, and hence, is a global health problem that causes the death of millions of people every year. One of the drugs used in tuberculosis treatment is isonicotinohydrazide (Isoniazid). In this study, N'-benzoylisonicotinohydrazide derivative compounds (a-l) were prepared using acylation reactions between isonicotinohydrazide and benzoyl chloride derivatives, employing the reflux method. Molecular docking studies suggested that all of the compounds had better interaction with Mycobactarium tuberculosis enoyl-acyl carrier protein reductase (InhA) than isonicotinohydrazide. It can be concluded that N'-benzoylisonicotinohydrazide derivatives (a-l) can be used as anti-tuberculosis candidates. The docking results obtained revealed that all of the compounds were interacted well with InhA, with compound g exhibiting the best interaction.

Design, Synthesis and Biological Evaluation of Some Triazole Schiff's Base Derivatives as Potential Antitubercular Agents.

Background:Tuberculosis (TB) is the second important cause of death worldwide caused by a bacterium called Mycobacterium tuberculosis. There is a need to find and develop new Anti-TB medications that are effective, inexpensive and suitable with human immunodeficiency virus and other anti-TB drugs used in many countries and mainly the developing countries where the disease is widespread. These drugs must be designed to shorten treatment time and to be active against resistant forms of the mycobacteria that will help to increase the patients compliance. A key compound which could be used as a lead to meet these requirements, is the thiolactomycin (TLM). This antibiotic which is naturally available has an ability to treat M. tuberculosis by inhibiting condensing enzymes called FAS II (mtFabH, KasA and KasB) which are related to biosynthesis of mycolic acid.Methods: Our main aims are to design and synthesize analogues of TLM as new lead molecules which could be a possible anti–TB candidate. To overcome the synthetic challenges associated with preparing the chiral TLM analogues; we synthesized and investigated a series of triazole analogues as inhibitors of KasA enzyme and the whole cell Mycobacteria. A series of twelve compounds were synthesized, purified and fully characterized using several spectroscopic techniques. Molecular modelling studies for our synthesised compounds were achieved by using a modelling program called AutoDock 4.2 utilising rigid docking.Results: Our results indicate that analogues of TLM show a good activity as compared to TLM.Conclusion:The activity obtained for the synthesized compounds against Mycobacteria tuberculosis indicate that the synthesised compounds 1, 2, 6 and 9 are pharmacologically active as they restrained the growth of the Mycobacteria bacteria.

Biochemical Potential of α-L-Arabinofuranosidase as Anti-Tuberculosis Candidate

Mycobacterium tuberculosis (MTB), the main causative organism of tuberculosis (TB), is a successful pathogen that overcomes the numerous challenges presented by the immune system of the host. The situation regarding control of tuberculosis has significantly worsened over the last decade with the spread of strains resistant to multiple antimycobacterial agents. Mycobacterial cell wall has potential as a target for developing protein therapeutic enzybiotic to overcome resistancy case in TB. One of the compiler of mycobacterial cell wall is arabinogalactan which is compiled by arabinose with unusual stereochemical. α-L-arabinofuranosidase (Abfa) is an enzyme that can breakdown arabinofuranosidic bond. However, its ability to breakdown the arabinofuranosidic from D-arabinose as monomer is still unknown. Here we present protein engineering through computational design to improve the specificity of Abfa by replacing discriminate amino acid residue. The effort is done to analyze the ability of Abfa in hydrolyzed mycobacterial cell wall and also to analyze the anti-TB assay of Abfa.

Enantiopure antituberculosis candidates synthesized from (−)-fenchone

The synthesis of new enantiopure N-acyl compounds derived from (−)-fenchone has been performed. The evaluation of their in vitro activity against Mycobacterium tuberculosis H37Rv showed for most of them moderate activity. The structures bearing sulfonamide functionality have comparable activity to ethambutol and possess low cytotoxicity.

Reinforcing the membrane-mediated mechanism of action of the anti-tuberculosis candidate drug thioridazine with molecular simulations

Thioridazine is a well-known dopamine-antagonist drug with a wide range of pharmacological properties ranging from neuroleptic to antimicrobial and even anticancer activity. Thioridazine is a critical component of a promising multi-drug therapy against M. tuberculosis. Amongst the various proposed mechanisms of action, the cell membrane-mediated one is peculiarly tempting due to the distinctive feature of phenothiazine drug family to accumulate in selected body tissues. In this study, we employ long-scale molecular dynamics simulations to investigate the interactions of three different concentrations of thioridazine with zwitterionic and negatively charged model lipid membranes. Thioridazine partitions into the interfacial region of membranes and modifies their structural and dynamic properties, however dissimilarly so at the highest membrane-occurring concentration, that appears to be obtainable only for the negatively charged bilayer. We show that the origin of such changes is the drug induced decrease of the interfacial tension, which ultimately leads to the significant membrane expansion. Our findings support the hypothesis that the phenothiazines therapeutic activity may arise from the drug-membrane interactions, and reinforce the wider, emerging view of action of many small, bioactive compounds.

NMR elucidation of novel SQ109 derivatives

The NMR elucidation of five novel SQ109 analogues including SQ109 is reported herein. These derivatives were synthesized as potential anti-tuberculosis candidates. One-dimensional NMR (1H and 13C) techniques show a series of overlapping signals from the methine and methylene groups of these compounds, thereby making it extremely difficult to assign all NMR signals. Two-dimensional (2D) NMR techniques were instrumental in overcoming these challenges. This paper appears to be a rare report on the complete structure elucidation of mono-substituted adamantane moieties.

Synthesis and evaluation of SQ109 analogues as potential anti-tuberculosis candidates

As part of an ongoing project to develop highly potent anti-tuberculosis therapeutics, six SQ109 derivatives were synthesized and screened in vitro for their anti-tuberculosis activity against the ATCC strain H37Rv and the extensively drug-resistant clinical strain XDR 173. Compound 16 with an extended alkene chain was the most active against both strains of Mycobacterium tuberculosis within a MIC range of 0.5–0.25 μM. Compound 12 and SQ109 were potent within a MIC range of 1–0.5 μM, whilst compound 18 displayed an activity within the MIC range of 0.5–2 μM against both Mycobacterium tuberculosis strains.