抗结核药物最新进展

结核病是病死率仅次于艾滋病的全球第二大感染性疾病。当前结核病的控制面临一系列挑战。世界卫生组织推荐的结核治疗方案疗程长,对敏感菌和耐药菌感染分别需6个月、20个月的持续治疗。现有抗结核一线化疗药仍为四十多年前所开发,品种有限,选择余地小。此外,多耐药结核病(MDR-TB)及广泛耐药结核病(XDR-TB)的流行,严重阻碍了结核病控制的进展。严峻的结核病防治形势急需抗结核新药的出现。近十年来,抗结核化疗新药研发在沉寂多年后取得了较明显进展。本文介绍了近年上市与处于临床及临床前研究阶段的抗结核新药。     

Discovery and optimization of benzotriazine di-N-oxides targeting replicating and nonreplicating Mycobacterium tuberculosis

Compounds bactericidal against both replicating and nonreplicating Mtb may shorten the length of TB treatment regimens by eliminating infections more rapidly. Screening of a panel of antimicrobial and anticancer drug classes that are bioreduced into cytotoxic species revealed that 1,2,4-benzotriazine di-N-oxides (BTOs) are potently bactericidal against replicating and nonreplicating Mtb. Medicinal chemistry optimization, guided by semiempirical molecular orbital calculations, identified a new lead compound (20q) from this series with an MIC of 0.31 μg/mL against H37Rv and a cytotoxicity (CC(50)) against Vero cells of 25 μg/mL. 20q also had equivalent potency against a panel of single-drug resistant strains of Mtb and remarkably selective activity for Mtb over a panel of other pathogenic bacterial strains. 20q was also negative in a L5178Y MOLY assay, indicating low potential for genetic toxicity. These data along with measurements of the physiochemical properties and pharmacokinetic profile demonstrate that BTOs have the potential to be developed into a new class of antitubercular drugs.     

Synthesis, biological evaluation, and molecular modeling of chalcone derivatives as potent inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatases (PtpA and PtpB)

Tuberculosis (TB) is a major infectious disease caused by Mycobacterium tuberculosis (Mtb). According to the World Health Organization (WHO), about 1.8 million people die from TB and 10 million new cases are recorded each year. Recently, a new series of naphthylchalcones has been identified as inhibitors of Mtb protein tyrosine phosphatases (PTPs). In this work, 100 chalcones were designed, synthesized, and investigated for their inhibitory properties against MtbPtps. Structure-activity relationships (SAR) were developed, leading to the discovery of new potent inhibitors with IC(50) values in the low-micromolar range. Kinetic studies revealed competitive inhibition and high selectivity toward the Mtb enzymes. Molecular modeling investigations were carried out with the aim of revealing the most relevant structural requirements underlying the binding affinity and selectivity of this series of inhibitors as potential anti-TB drugs.     

Opportunities for overcoming tuberculosis: Emerging targets and their inhibitors

Tuberculosis (TB), an airborne infectious disease mainly caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of human morbidity and mortality worldwide. Given the alarming rise of resistance to anti-TB drugs and latent TB infection (LTBI), new targets and novel bioactive compounds are urgently needed for the treatment of this disease. We provide an overview of the recent advances in anti-TB drug discovery, emphasizing several newly validated targets for which an inhibitor has been reported in the past five years. Our review presents several attractive directions that have potential for the development of next-generation therapies.     

Emerging technologies for monitoring drug-resistant tuberculosis at the point-of-care

Infectious diseases are the leading cause of death worldwide. Among them, tuberculosis (TB) remains a major threat to public health, exacerbated by the emergence of multiple drug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis (Mtb). MDR-Mtb strains are resistant to first-line anti-TB drugs such as isoniazid and rifampicin; whereas XDR-Mtb strains are resistant to additional drugs including at least to any fluoroquinolone and one of the second-line anti-TB injectable drugs such as kanamycin, capreomycin, or amikacin. Clinically, these strains have significantly impacted the management of TB in high-incidence developing countries, where systemic surveillance of TB drug resistance is lacking. For effective management of TB on-site, early detection of drug resistance is critical to initiate treatment, to reduce mortality, and to thwart drug-resistant TB transmission. In this review, we discuss the diagnostic challenges to detect drug-resistant TB at the point-of-care (POC). Moreover, we present the latest advances in nano/microscale technologies that can potentially detect TB drug resistance to improve on-site patient care.     

Type II NADH: menaquinone oxidoreductase of Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb) remains the deadliest bacterial pathogen worldwide, causing an estimated 1.7 million deaths in 2004 among an infected population of approximately 2 billion people, according to the World Health Organization (WHO). Therapeutic options are limited to a few drugs that are becoming increasingly ineffective. Multidrug-resistant (MDR) Mtb strains are prevalent globally, fueled by inadequate patient compliance of drug intake. Recently, a high incidence of extensively drug-resistant (XDR) strains resistant to all currently used drugs was reported among patients with the human immunodeficiency virus (HIV) in KwaZulu Natal, South Africa [1]. The high mortality rate and short survival time of patients with XDR Mtb was especially alarming. The emergence of XDR mycobacteria emphasizes the urgent need for the identification of novel targets and development of new drugs. New potential drug targets exist in the Mtb respiratory chain. Certain classes of drugs have long been shown to exert significant tuberculocidal activity, such as the phenothiazines [2, 3]. Phenothiazines inhibit one of the key enzymes of the respiratory chain; type II NADH:menaquinone oxidoreductase or NDH-2 [4]. The effectiveness of this class of drugs against Mtb justifies further research into the respiratory chain, with the aim of elucidating its physiologic roles in in vitro and in vivo survival, and discovering new (sub)classes of drugs that can safely serve as inhibitors for clinical use. In this chapter, we critically review the recent advances in this field, with particular emphasis on NDH-2, and underscore the kinds of research further needed for drug development.     

Evaluation of in-vitro leishmanicidal activity of hydrazones of thiophene carboxaldehydes against promastigotes of Leishmania infantum and Leishmania tropica.

The lack of leishmanicidal drugs has prompted the synthesis and testing of new hydrazones of thiophene carboxaldehydes against three Leishmania strains. The compounds were obtained by condensation of appropriate hydrazines with thiophene 2-carboxaldehyde (series 1), thiophene 3-carboxaldehyde (series 2), and 5-nitrothiophene-2-carboxaldehyde (series 3). Leishmanicidal activity was assessed against promastigotes of Leishmania strains, grown in-vitro in nutrient broth medium complemented with fresh rabbit blood. The minimal inhibitory concentrations were evaluated against pentamidine, as a reference drug. Several compounds exhibited significant leishmanicidal activity, the best being ten times more active than pentamidine.     

Novel trisubstituted benzimidazoles, targeting Mtb FtsZ, as a new class of antitubercular agents

Libraries of novel trisubstituted benzimidazoles were created through rational drug design. A good number of these benzimidazoles exhibited promising MIC values in the range of 0.5-6 μg/mL (2-15 μM) for their antibacterial activity against Mtb H37Rv strain. Moreover, five of the lead compounds also exhibited excellent activity against clinical Mtb strains with different drug-resistance profiles. All lead compounds did not show appreciable cytotoxicity (IC(50) > 200 μM) against Vero cells, which inhibited Mtb FtsZ assembly in a dose dependent manner. The two lead compounds unexpectedly showed enhancement of the GTPase activity of Mtb FtsZ. The result strongly suggests that the increased GTPase activity destabilizes FtsZ assembly, leading to efficient inhibition of FtsZ polymerization and filament formation. The TEM and SEM analyses of Mtb FtsZ and Mtb cells, respectively, treated with a lead compound strongly suggest that lead benzimidazoles have a novel mechanism of action on the inhibition of Mtb FtsZ assembly and Z-ring formation.     

Stereochemistry at the forefront in the design and discovery of novel anti-tuberculosis agents

Today, 75% of new drugs introduced to the market are single enantiomers and new techniques in asymmetric synthesis and chiral separation expedites chiral drug discovery and development worldwide. The enantiomers of a chiral drug present unique chemical and pharmacological behaviors in a chiral environment, such as the human body, in which the stereochemistry of chiral drugs determines their pharmacokinetic, pharmacodynamic, and toxicological actions. Thus, it is imperative that only the pure and therapeutically active isomer be prepared and marketed. Tuberculosis (TB), a highly contagious and airborne disease that is caused by infection with Mycobacterium tuberculosis (Mtb), currently represents one of the most threatening health problems globally. The emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), as well as HIV co-infection along with a lengthy treatment regimen, highlights an urgent need for the development of new anti-TB agents. Currently, new chiral anti-TB agents are being developed from some well-known anti-TB agents, high throughput screening (HTS) hits, and natural products. This review will focus on the reported chiral anti-TB agents together with the clinical importance of their chirality and stereochemistry.     

In vitro evaluation of dinactin,a potent microbial metabolite against Mycobacterium tuberculosis

Current long duration treatment options and the emergence of drug resistance in tuberculosis (TB) have led to renewed interest in discovery of novel anti-tubercular agents or the scaffolds exhibiting enhanced efficacy with current anti-TB drugs. Herein, dinactin, a potent bioactive macrotetrolide isolated from Streptomyces puniceus AS13, was evaluated against Mycobacterium tuberculosis H37Rv and other susceptible and drug-resistant clinical isolates of M. tuberculosis. In vitro pharmacological assays showed that dinactin is bactericidal against laboratory standard strain M. tuberculosis H37Rv (minimum inhibitory concentration [MIC] 1 µg/mL and minimum bactericidal concentration [MBC] 4 µg/mL). Dinactin also retained its activity against various clinical isolates, including multidrug-resistant strains of M. tuberculosis. Whole cell interaction assays with standard first- and second-line anti-TB drugs showed the synergistic interaction of dinactin with rifampicin or amikacin, reflecting its suitability for use in combination regimens. The killing kinetics studies of dinactin against M. tuberculosis H37Rv revealed that it has strong concentration-dependent anti-TB activity that is also dependent on time. The kill curve also showed dynamic killing capacity of dinactin as it exhibited bactericidal potential at all concentrations tested. Kill curve data demonstrated that dinactin, like isoniazid, exerts its strong tuberculocidal activity within the first two days of exposure. This evidence strongly supports further evaluation of dinactin as a new option in the treatment of TB.     

Identification and characterization of novel inhibitors of mPTPB, an essential virulent phosphatase from Mycobacterium tuberculosis

Mycobacterium protein tyrosine phosphatase B (mPTPB) is an essential virulence factor required for Mycobacterium tuberculosis (Mtb) survival in host macrophages. Consequently, mPTPB represents an exciting new target with a completely novel mechanism of action. We screened a library of 7,500 compounds against mPTPB and identified several 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide and piperazinyl-thiophenyl-ethyl-oxalamide derivatives as two distinct classes of mPTPB inhibitors. We showed that both classes of inhibitors are capable of blocking the mPTPB-mediated ERK1/2 inactivation. We further demonstrated that both classes of mPTPB inhibitors are effective in inhibiting the growth of Mtb in macrophages. Thus, improvement of the lead compounds may produce a novel class of anti-TB agents.     

Novel peptidomimetic peptide deformylase (PDF) inhibitors of Mycobacterium tuberculosis

Emergence of MDR‐TB and XDR‐TB led to the failure of available anti‐tubercular drugs. In order to explore, identify and develop new anti‐tubercular drugs, novel peptidomimetic series of Mtb–peptide deformylase (PDF) inhibitors was designed and synthesized. In vitro antimycobacterial potential of compounds was established by screening of compounds against Mycobacterium tuberculosis H37Rv strain using MABA. Among them, ester series of compounds 4a , 4b , 4c , 4d , and 4e were found most active, with compound 4c being highly active and exhibiting minimum inhibitory concentration of 6.25 µg/ml against M. tb H37Rv strain. Additionally, the compounds were docked to determine the probable binding interactions and understand the mechanism of action of most active molecules on Mtb‐peptide deformylase (PDF), which is involved in the mycobacterium protein synthesis.     

Design,Synthesis, and Biological Evaluation of Pyrazolo[1,5-a]pyridine-3-carboxamides as Novel Antitubercular Agents

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Design, synthesis, and biological evaluation of new cinnamic derivatives as antituberculosis agents

Tuberculosis, HIV coinfection with TB, emergence of multidrug-resistant TB, and extensively drug-resistant TB are the major causes of death from infectious diseases worldwide. Because no new drug has been introduced in the last several decades, new classes of molecules as anti-TB drugs are urgently needed. Herein, we report the synthesis and structure-activity relationships of a series of thioester, amide, hydrazide, and triazolophthalazine derivatives of 4-alkoxy cinnamic acid. Many compounds exhibited submicromolar minimum inhibitory concentrations against Mycobacterium tuberculosis strain (H(37)Rv). Interestingly, compound 13e, a 4-isopentenyloxycinnamyl triazolophthalazine derivative, was found to be 100-1800 times more active than isoniazid (INH) when tested for its ability to inhibit the growth of INH-resistant M. tuberculosis strains. The results also revealed that 13e does not interfere with mycolic acid biosynthesis, thereby pointing to a different mode of action and representing an attractive lead compound for the development of new anti-TB agents.     

Combining Cheminformatics Methods and Pathway Analysis to Identify Molecules with Whole-Cell Activity Against Mycobacterium Tuberculosis

Purpose

New strategies for developing inhibitors of Mycobacterium tuberculosis (Mtb) are required in order to identify the next generation of tuberculosis (TB) drugs. Our approach leverages the integration of intensive data mining and curation and computational approaches, including cheminformatics combined with bioinformatics, to suggest biological targets and their small molecule modulators.

Methods

We now describe an approach that uses the TBCyc pathway and genome database, the Collaborative Drug Discovery database of molecules with activity against Mtb and their associated targets, a 3D pharmacophore approach and Bayesian models of TB activity in order to select pathways and metabolites and ultimately prioritize molecules that may be acting as substrate mimics and exhibit activity against TB.

Results

In this study we combined the TB cheminformatics and pathways databases that enabled us to computationally search >80,000 vendor available molecules and ultimately test 23 compounds in vitro that resulted in two compounds (N-(2-furylmethyl)-N??-[(5-nitro-3-thienyl)carbonyl]thiourea and N-[(5-nitro-3-thienyl)carbonyl]-N??-(2-thienylmethyl)thiourea) proposed as mimics of D-fructose 1,6 bisphosphate, (MIC of 20 and 40???g/ml, respectively).

Conclusion

This is a simple yet novel approach that has the potential to identify inhibitors of bacterial growth as illustrated by compounds identified in this study that have activity against Mtb.     

The antimycobacterial MICs, SARs, and QSARs of some ethnobotanically selected phytocompounds

Forty ethnobotanically selected phytocompounds and four conventional TB treatment drugs were screened for their in vitro inhibitory activity against two strains of Mycobacterium tuberculosis. Compounds with better minimum inhibitory concentrations (MICs), than that of any of the four conventional TB treatment drugs, were identified as promising leads. The study identified six promising leads; three benzoquinones (114, 121, and 116), a flavone (141), an isoflavone (145), and an alkaloid (151). Structure–activity relationships (SARs) and quantitative structure–activity relationships (QSARs) were generated for the flavonoid and the benzoquinone series members. QSARs were used in the prediction of structural modifications necessary for activity improvement and in the prediction of activity of untested compounds.     

Fluoroquinolones and tuberculosis

Tuberculosis (TB) remains one of the main causes of morbidity worldwide, and the emergence of multi-drug resistant (MDR) Mycobacterium tuberculosis strains in some parts of the world has become a major concern. The decrease in activity of the major anti-TB drugs, such as isoniazid and rifampicin, is an important threat and alternative therapies are urgently required. The anti-TB activity of the fluoroquinolones has been under investigation since the 1980s. Many are active in vitro but only a few, including ofloxacin, ciprofloxacin, sparfloxacin, levofloxacin and lomefloxacin, have been clinically tested. Fluoroquinolones can be used in co-therapy with the available anti-TB drugs. However, the choice of fluoroquinolone should be based not only on the in vitro activity, but also on the long-term tolerance. Fluoroquinolones are novel anti-TB drugs to be used when a patient is infected with a MDR-TB strain.     

Substituted Xanthones as Antimycobacterial Agents,Part 2: Antimycobacterial Activity

A series of substituted xanthones was tested for their activity against four mycobacterial strains (Mycobacterium tuberculosis, M. avium, M. lufu, M. smegmatis) by determination of the minimum inhibitory concentrations (MIC values). For the most active compounds, supplementary characterisation was performed by bacterial growth kinetics, which allows a more precise interpretation of their antimycobacterial effects. From the test set, 1-methyl-2,4,7-trinitroxanthone ( 8a ) showed the highest antimycobacterial activity with a MIC value of 3 μg/mL against M. tuberculosis, which is comparable to the effect of well known drugs used in the treatment of tuberculosis. For all other compounds, the MIC values could not be determined, due to the comparatively low activity and to the poor solubility of the compounds, respectively. The semiquantitative evaluation of activity against the different strains of mycobacteria resulted in a classification into three activity classes, which will be used as dependent parameter in QSAR investigations, to be published in Part 3 of this series.     

Fluoroquinolones and tuberculosis

Tuberculosis (TB) remains one of the main causes of morbidity worldwide, and the emergence of multi-drug resistant (MDR) Mycobacterium tuberculosis strains in some parts of the world has become a major concern. The decrease in activity of the major anti-TB drugs, such as isoniazid and rifampicin, is an important threat and alternative therapies are urgently required. The anti-TB activity of the fluoroquinolones has been under investigation since the 1980s. Many are active in vitro but only a few, including ofloxacin, ciprofloxacin, sparfloxacin, levofloxacin and lomefloxacin, have been clinically tested. Fluoroquinolones can be used in co-therapy with the available anti-TB drugs. However, the choice of fluoroquinolone should be based not only on the in vitro activity, but also on the long-term tolerance. Fluoroquinolones are novel anti-TB drugs to be used when a patient is infected with a MDR-TB strain.