opc-67683 and Tuberculosis

Tuberculosis (TB) continues to claim the lives of around 1.7 million people per year. Most concerning are the reports of multidrug drug resistance. Paradoxically, this global health pandemic is demanding new therapies when resources and interest are waning. However, continued tuberculosis drug discovery is critical to address the global health need and burgeoning multidrug resistance. Many diverse classes of antitubercular compounds have been identified with activity in vitro and in vivo. Our analyses of over 100 active leads are representative of thousands of active compounds generated over the past decade, suggests that they come from few chemical classes or natural product sources. We are therefore repeatedly identifying compounds that are similar to those that preceded them. Our molecule-centered cheminformatics analyses point to the need to dramatically increase the diversity of chemical libraries tested and get outside of the historic

Topics: Antitubercular Agents; Bacterial Proteins; Drug Discovery; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Nitroimidazoles; Nucleoside-Phosphate Kinase; Structure-Activity Relationship; Tuberculosis

The Lancet Respiratory Medicine Commission on drug-resistant tuberculosis was published in 2017, which comprehensively reviewed and provided recommendations on various aspects of the disease. Several key new developments regarding drug-resistant tuberculosis are outlined in this Commission Update. The WHO guidelines on treating drug-resistant tuberculosis were updated in 2019 with a reclassification of second line anti-tuberculosis drugs. An injection-free MDR tuberculosis treatment regimen is now recommended. Over the past 3 years, advances in treatment include the recognition of the safety and mortality benefit of bedaquiline, the finding that the 9-11 month injectable-based 'Bangladesh' regimen was non-inferior to longer regimens, and promising interim results of a novel 6 month 3-drug regimen (bedaquiline, pretomanid, and linezolid). Studies of explanted lungs from patients with drug-resistant tuberculosis have shown substantial drug-specific gradients across pulmonary cavities, suggesting that alternative dosing and drug delivery strategies are needed to reduce functional monotherapy at the site of disease. Several controversies are discussed including the optimal route of drug administration, optimal number of drugs constituting a regimen, selection of individual drugs for a regimen, duration of the regimen, and minimal desirable standards of antibiotic stewardship. Newer rapid nucleic acid amplification test platforms, including point-of-care systems that facilitate active case-finding, are discussed. The rapid diagnosis of resistance to other drugs, (notably fluoroquinolones), and detection of resistance by targeted or whole genome sequencing will probably change the diagnostic landscape in the near future.

Topics: Antitubercular Agents; Diarylquinolines; Drug Therapy, Combination; Humans; Linezolid; Nitroimidazoles; Oxazoles; Periodicals as Topic; Pulmonary Medicine; Societies, Medical; Tuberculosis; Tuberculosis, Multidrug-Resistant

Tuberculosis (TB) is a devastating threat to human health whose treatment without the emergence of drug resistant Mycobacterium tuberculosis (M. tuberculosis) is the million-dollar question at present. The pathogenesis of M. tuberculosis has been extensively studied which represents unique defence strategies by infecting macrophages. Several anti-tubercular drugs with varied mode of action and administration from diversified sources have been used for the treatment of TB that later contributed to the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). However, few of potent anti-tubercular drugs are scheduled for clinical trials status in 2017-2018. Peptides of varied origins such as human immune cells and non-immune cells, bacteria, fungi, and venoms have been widely investigated as anti-tubercular agents for the replacement of existing anti-tubercular drugs in future. In the present review, we spotlighted not only on the mechanisms of action and mode of administration of currently available anti-tubercular drugs but also the recent comprehensive report of World Health Organization (WHO) on TB epidemic, diagnosis, prevention, and treatment. The major excerpt of the study also inspects the direct contribution of different computational tools during drug designing strategies against M. tuberculosis in order to grasp the interplay between anti-tubercular peptides and targeted bacterial protein. The potentiality of some of these anti-tubercular peptides as therapeutic agents unlocks a new portal for achieving the goal of end TB strategy.

Topics: Antitubercular Agents; Computational Biology; Diarylquinolines; Drug Design; Extensively Drug-Resistant Tuberculosis; Humans; Models, Molecular; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Peptides; Tuberculosis; Tuberculosis, Multidrug-Resistant; World Health Organization

Antituberculosis (anti-TB) treatment may be affected by both diabetes and hypoglycemic agents in patients with these 2 comorbidities. However, data supporting this conclusion relate only to standard anti-TB therapies. Sirturo

Topics: Aged; Animals; Antitubercular Agents; Arrhythmias, Cardiac; Comorbidity; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diarylquinolines; Drug Interactions; Drug Monitoring; Humans; Hypoglycemic Agents; Middle Aged; Nitroimidazoles; Oxazoles; Polypharmacy; Risk Assessment; Risk Factors; Tuberculosis

Recent advances in the development of new drugs and regimens provide hope that well tolerated, effective, and shorter-duration treatments for tuberculosis (TB) will become available. This review covers the recent trials of new TB drugs and regimens.. Moxifloxacin and levofloxacin have equally good efficacy and safety in the early phase of treatment of multidrug-resistant TB (MDR-TB), and linezolid has the potential to cure refractory cases of MDR-TB. Bedaquiline and delamanid may be the best drug candidates for enhancing treatment options for MDR-TB. New chemicals, such as sutezolid, AZD5847, PA-824, SQ109, and BTZ043, show potent activity against Mycobacterium tuberculosis. Late-generation fluoroquinolones in combination with the first-line and second-line anti-TB drugs have been used to shorten the treatment duration in drug-susceptible and MDR-TB.. New drugs and new combination regimens in clinical trials are expected to increase therapeutic efficacy and shorten treatment duration in both drug-susceptible and drug-resistant TB.

Topics: Acetamides; Adamantane; Antitubercular Agents; Clinical Trials as Topic; Diarylquinolines; Drug Administration Schedule; Drug Design; Ethylenediamines; Female; Fluoroquinolones; Humans; Levofloxacin; Linezolid; Male; Moxifloxacin; Nitroimidazoles; Oxazoles; Oxazolidinones; Spiro Compounds; Thiazines; Tuberculosis; Tuberculosis, Multidrug-Resistant

Topics: Antitubercular Agents; Aza Compounds; Cross-Sectional Studies; Diagnosis, Differential; Diarylquinolines; Fluoroquinolones; Germany; Humans; Moxifloxacin; Nitroimidazoles; Oxazoles; Prognosis; Quinolines; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

Tuberculosis is a major disease causing every year 1.8 million deaths worldwide and represents the leading cause of mortality resulting from a bacterial infection. Introduction in the 60's of first-line drug regimen resulted in the control of the disease and TB was perceived as defeating. However, since the progression of HIV leading to co-infection with AIDS and the emergence of drug resistant strains, the need of new anti-tuberculosis drugs was not overstated. However in the past 40 years any new molecule did succeed in reaching the market. Today, the pipeline of potential new treatments has been fulfilled with several compounds in clinical trials or preclinical development with promising activities against sensitive and resistant Mycobacterium tuberculosis strains. Compounds as gatifloxacin, moxifloxacin, metronidazole or linezolid already used against other bacterial infections are currently evaluated in clinical phases 2 or 3 for treating tuberculosis. In addition, analogues of known TB drugs (PA-824, OPC-67683, PNU-100480, AZD5847, SQ609, SQ109, DC-159a) and new chemical entities (TMC207, BTZ043, DNB1, BDM31343) are under development. In this review, we report the chemical synthesis, mode of action when known, in vitro and in vivo activities and clinical data of all current small molecules targeting tuberculosis.

Topics: Animals; Antitubercular Agents; Clinical Trials as Topic; Drug Discovery; Humans; Tuberculosis

Topics: Animals; Antitubercular Agents; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical; Drug Resistance, Bacterial; Fluoroquinolones; Humans; Mycobacterium tuberculosis; Rifamycins; Tuberculosis

Topics: Animals; Antitubercular Agents; Humans; Nitroimidazoles; Oxazoles; Treatment Outcome; Tuberculosis

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Cyclodextrins; Humans; Lung; Solubility; Tuberculosis; Tuberculosis, Pulmonary

Antimicrobial susceptibility testing, based on clinical breakpoints that incorporate pharmacokinetics/pharmacodynamics (PK/PD) and clinical outcomes, is becoming a new standard in guiding individual patient therapy as well as for drug resistance surveillance. However, for most antituberculosis drugs, breakpoints are instead defined by the epidemiological cutoff values of the MIC of phenotypically wild-type strains irrespective of PK/PD or dose. In this study, we determined the PK/PD breakpoint for delamanid by estimating the probability of target attainment for the approved dose administered at 100 mg twice daily using Monte Carlo experiments. We used the PK/PD targets (0- to 24-h area under the concentration-time curve to MIC) identified in a murine chronic tuberculosis model, hollow fiber system model of tuberculosis, early bactericidal activity studies of patients with drug-susceptible tuberculosis, and population pharmacokinetics in patients with tuberculosis. At the MIC of 0.016 mg/L, determined using Middlebrook 7H11 agar, the probability of target attainment was 100% in the 10,000 simulated subjects. The probability of target attainment fell to 25%, 40%, and 68% for PK/PD targets derived from the mouse model, the hollow fiber system model of tuberculosis, and patients, respectively, at the MIC of 0.031 mg/L. This indicates that an MIC of 0.016 mg/L is the delamanid PK/PD breakpoint for delamanid at 100 mg twice daily. Our study demonstrated that it is feasible to use PK/PD approaches to define a breakpoint for an antituberculosis drug.

Topics: Animals; Anti-Bacterial Agents; Antitubercular Agents; Mice; Microbial Sensitivity Tests; Monte Carlo Method; Tuberculosis

A recent landmark trial showed a 4-month regimen of rifapentine, pyrazinamide, moxifloxacin, and isoniazid (PZMH) to be noninferior to the 6-month standard of care. Here, two murine models of tuberculosis were used to test whether novel regimens replacing rifapentine and isoniazid with bedaquiline and another drug would maintain or increase the sterilizing activity of the regimen. In BALB/c mice, replacing rifapentine in the PZM backbone with bedaquiline (i.e., BZM) significantly reduced both lung CFU counts after 1 month and the proportion of mice relapsing within 3 months after completing 1.5 months of treatment. The addition of rifabutin to BZM (BZMRb) further increased the sterilizing activity. In the C3HeB/FeJ mouse model characterized by caseating lung lesions, treatment with BZMRb resulted in significantly fewer relapses than PZMH after 2 months of treatment. A regimen combining the new DprE1 inhibitor OPC-167832 and delamanid (BZOD) also had superior bactericidal and sterilizing activity compared to PZM in BALB/c mice and was similar in efficacy to PZMH in C3HeB/FeJ mice. Thus, BZM represents a promising backbone for treatment-shortening regimens. Given the prohibitive drug-drug interactions between bedaquiline and rifampin or rifapentine, the BZMRb regimen represents the best opportunity to combine, in one regimen, the treatment-shortening potential of the rifamycin class with that of BZM and deserves high priority for evaluation in clinical trials. Other 4-drug BZM-based regimens and BZOD represent promising opportunities for extending the spectrum of treatment-shortening regimens to rifamycin- and fluoroquinolone-resistant tuberculosis.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Diarylquinolines; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Isoniazid; Mice; Mice, Inbred BALB C; Moxifloxacin; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Pyrazinamide; Rifabutin; Tuberculosis

Apart from bactericidal effects, anti-tuberculosis drugs can interfere with the host's immune system. In this study, we analyzed the role of delamanid (DLM), an inhibitor of mycolic acid synthesis of mycobacterial cell wall, on human macrophages.. Based on a cohort of multidrug-resistant tuberculosis (MDR-TB) patients treated with DLM, the levels of C-reaction protein (CRP) and cytokines in the plasma were monitored using immunoturbidimetric assay and flow cytometry, respectively. We investigated the role of DLM on CXCL10 expression in U937 cell model using the following methods: cell viability assay, reverse transcription-quantitative polymerase chain reaction, enzyme linked immunosorbent assay, immunoblot, and transwell co-culture assay.. A total of 23 MDR-TB patients were included, comprising of 13 patients treated with optimized background therapeutic regimen (OBR) plus DLM regimen (OBR+DLM) and 10 patients treated with OBR plus placebo. DLM administration was associated with a significant reduce in circulating CRP level. Correspondingly, after treatment, the level of CXCL10 in patients treated with OBR+DLM was significantly lower than that with control. Using cell model, DLM dramatically suppressed CXCL10 expression, which majorly depended on inhibiting the JAK/STAT pathway, and impaired the migration of PBMCs.

Topics: Chemokine CXCL10; Humans; Inflammation; Janus Kinases; Signal Transduction; STAT Transcription Factors; STAT1 Transcription Factor; Tuberculosis; Tuberculosis, Multidrug-Resistant; U937 Cells

The treatment success rate of drug-resistant (DR) tuberculosis is alarmingly low. Therefore, more effective and less complex regimens are urgently required.. We compared the efficacy of an all oral DR tuberculosis drug regimen consisting of bedaquiline (25 mg/kg), delamanid (2.5 mg/kg), and linezolid (100 mg/kg) (BDL) on the mycobacterial load in the lungs and spleen of tuberculosis-infected mice during a treatment period of 24 weeks. This treatment was compared with the standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE). Relapse was assessed 12 weeks after treatment. Two logistic regression models were developed to compare the efficacy of both regimens.. Culture negativity in the lungs was achieved at 8 and 20 weeks of treatment with BDL and HRZE, respectively. After 14 weeks of treatment only 1 mouse had relapse in the BDL group, while in the HRZE group relapse was still observed at 24 weeks of treatment. Predictions from the final mathematical models showed that a 95% cure rate was reached after 20.5 and 28.5 weeks of treatment with BDL and HRZE, respectively.. The BDL regimen was observed to be more effective than HRZE and could be a valuable option for the treatment of DR tuberculosis.

Topics: Animals; Antitubercular Agents; Diarylquinolines; Disease Models, Animal; Drug Therapy, Combination; Linezolid; Mice; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Pyrazinamide; Recurrence; Tuberculosis

New all-oral regimens for rifampin-resistant tuberculosis (RR-TB) are being scaled up globally. Measurement of drug concentrations in hair assesses long-term drug exposure. Delamanid (DLM) is likely to be a key component of future RR-TB treatment regimens, but a method to describe its quantification in hair via liquid chromatography-tandem mass spectrometry (LC-MS/MS) has not previously been described. We developed and validated a simple, fast, sensitive, and accurate LC-MS/MS method for quantifying DLM and its metabolite DM-6705 in small hair samples. We pulverized and extracted two milligrams of hair in methanol at 37 °C for two hours, and diluted 1:1 with water. A gradient elution method eluted DLM, DM-6705, and the internal standard OPC 14714 within 3 min, bringing overall analysis time to 5.5 min. The method has limits of detection (LOD) of 0.0003 ng/mg for DLM and 0.003 ng/mg for DM-6705. The established linear dynamic ranges are 0.003-2.1 ng/mg and 0.03-21 ng/mg for DLM and DM-6705, respectively. Eleven of 12 participant hair samples had concentrations within DLM's linear dynamic range, while all 12 samples had concentrations within the quantifiable range for DM-6705. The ranges of concentrations observed in these clinical samples for DLM and DM-6705 were 0.004-0.264 ng/mg hair and 0.412-12.041 ng/mg hair respectively. We demonstrate that while DLM was detected in hair at very low levels, its primary metabolite DM-6705 had levels approximately 100 times higher. Measuring DM-6705 in hair may accurately reflect long-term adherence to DLM-containing regimens for drug-resistant TB.

Topics: Chromatography, Liquid; Hair; Humans; Limit of Detection; Linear Models; Nitroimidazoles; Oxazoles; Reproducibility of Results; Tandem Mass Spectrometry; Tuberculosis; Tuberculosis, Multidrug-Resistant

Delamanid has been studied extensively and approved for the treatment of pulmonary multidrug-resistant tuberculosis; however, its potential in the treatment of extrapulmonary tuberculosis remains unknown. We previously reported that, in rats, delamanid was broadly distributed to various tissues in addition to the lungs. In this study, we simulated human plasma concentration-time courses (pharmacokinetic profile) of delamanid, which has a unique property of metabolism by albumin, using two different approaches (steady-state concentration of plasma-mean residence time [

Topics: Animals; Antitubercular Agents; Dogs; Humans; Mice; Models, Biological; Nitroimidazoles; Oxazoles; Rats; Tuberculosis

The World Health Organization launched a global initiative, known as aDSM (active TB drug safety monitoring and management) to better describe the safety profile of new treatment regimens for drug-resistant tuberculosis (TB) in real-world settings. However, comprehensive surveillance is difficult to implement in several countries. The aim of the aDSM project is to demonstrate the feasibility of implementing national aDSM registers and to describe the type and the frequency of adverse events (AEs) associated with exposure to the new anti-TB drugs. Following a pilot study carried out in 2016, official involvement of TB reference centres/countries into the project was sought and cases treated with bedaquiline- and/or delamanid-containing regimens were consecutively recruited. AEs were prospectively collected ensuring potential attribution of the AE to a specific drug based on its known safety profile. A total of 309 cases were fully reported from 41 centres in 27 countries (65% males; 268 treated with bedaquiline, 20 with delamanid, and 21 with both drugs) out of an estimated 781 cases the participating countries had committed to report by the first quarter of 2019.

Topics: Antitubercular Agents; Diarylquinolines; Drug Therapy, Combination; Feasibility Studies; Female; Humans; Male; Nitroimidazoles; Oxazoles; Pilot Projects; Tuberculosis; Tuberculosis, Multidrug-Resistant; World Health Organization

Topics: Antitubercular Agents; Clofazimine; Diarylquinolines; Drug Resistance, Multiple, Bacterial; Humans; Linezolid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Reproducibility of Results; Tuberculosis; Tuberculosis, Multidrug-Resistant

As part of a quest for backups to the antitubercular drug pretomanid (PA-824), we investigated the unexplored 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]-thiazoles and related -oxazoles. The nitroimidazothiazoles were prepared in high yield from 2-bromo-4-nitroimidazole via heating with substituted thiiranes and diisopropylethylamine. Equivalent examples of these two structural classes provided broadly comparable MICs, with 2-methyl substitution and extended aryloxymethyl side chains preferred; albeit, S-oxidised thiazoles were ineffective for tuberculosis. Favourable microsomal stability data for a biaryl thiazole (45) led to its assessment in an acute Mycobacterium tuberculosis mouse model, alongside the corresponding oxazole (48), but the latter proved to be more efficacious. In vitro screening against kinetoplastid diseases revealed that nitroimidazothiazoles were inactive versus leishmaniasis but showed interesting activity, superior to that of the nitroimidazooxazoles, against Chagas disease. Overall, "thio-delamanid" (49) is regarded as the best lead.

Topics: Animals; Antitubercular Agents; Chagas Disease; Disease Models, Animal; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Structure-Activity Relationship; Thiazoles; Tuberculosis

Topics: Antitubercular Agents; Diarylquinolines; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Global Health; Humans; Nitroimidazoles; Oxazoles; Tuberculosis

Nitroimidazoles are a promising new class of antitubercular agents. The nitroimidazo-oxazole delamanid (OPC-67683, Deltyba) is in phase III trials for the treatment of multidrug-resistant tuberculosis, while the nitroimidazo-oxazine PA-824 is entering phase III for drug-sensitive and drug-resistant tuberculosis. TBA-354 (SN31354[(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine]) is a pyridine-containing biaryl compound with exceptional efficacy against chronic murine tuberculosis and favorable bioavailability in preliminary rodent studies. It was selected as a potential next-generation antituberculosis nitroimidazole following an extensive medicinal chemistry effort. Here, we further evaluate the pharmacokinetic properties and activity of TBA-354 against Mycobacterium tuberculosis. TBA-354 is narrow spectrum and bactericidal in vitro against replicating and nonreplicating Mycobacterium tuberculosis, with potency similar to that of delamanid and greater than that of PA-824. The addition of serum protein or albumin does not significantly alter this activity. TBA-354 maintains activity against Mycobacterium tuberculosis H37Rv isogenic monoresistant strains and clinical drug-sensitive and drug-resistant isolates. Spontaneous resistant mutants appear at a frequency of 3 × 10(-7). In vitro studies and in vivo studies in mice confirm that TBA-354 has high bioavailability and a long elimination half-life. In vitro studies suggest a low risk of drug-drug interactions. Low-dose aerosol infection models of acute and chronic murine tuberculosis reveal time- and dose-dependent in vivo bactericidal activity that is at least as potent as that of delamanid and more potent than that of PA-824. Its superior potency and pharmacokinetic profile that predicts suitability for once-daily oral dosing suggest that TBA-354 be studied further for its potential as a next-generation nitroimidazole.

Topics: Animals; Antitubercular Agents; Caco-2 Cells; Cell Line, Tumor; Disease Models, Animal; Drug Interactions; Drug Resistance, Bacterial; Female; Humans; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitroimidazoles; Oxazines; Oxazoles; Tuberculosis

New regimens based on two or more novel agents are sought in order to shorten or simplify the treatment of both drug-susceptible and drug-resistant forms of tuberculosis. PA-824 is a nitroimidazo-oxazine now in phase II trials and has shown significant early bactericidal activity alone and in combination with the newly approved agent bedaquiline or with pyrazinamide with or without moxifloxacin. While the development of PA-824 continues, a potential next-generation derivative, TBA-354, has been discovered to have in vitro potency superior to that of PA-824 and greater metabolic stability than that of the other nitroimidazole derivative in clinical development, delamanid. In the present study, we compared the activities of PA-824 and TBA-354 as monotherapies in murine models of the initial intensive and continuation phases of treatment, as well as in combination with bedaquiline plus pyrazinamide, sutezolid, and/or clofazimine. The monotherapy studies demonstrated that TBA-354 is 5 to 10 times more potent than PA-824, but selected mutants are cross-resistant to PA-824 and delamanid. The combination studies revealed that TBA-354 is 2 to 4 times more potent than PA-824 when combined with bedaquiline, and when administered at a dose equivalent to that of PA-824, TBA-354 demonstrated superior sterilizing efficacy. Perhaps most importantly, the addition of either nitroimidazole significantly improved the sterilizing activities of bedaquiline and sutezolid, with or without pyrazinamide, confirming the value of each agent in this potentially universally active short-course regimen.

Topics: Animals; Antitubercular Agents; Clofazimine; Diarylquinolines; Disease Models, Animal; Drug Therapy, Combination; Female; Fluoroquinolones; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Moxifloxacin; Mycobacterium tuberculosis; Nitroimidazoles; Oxazines; Oxazoles; Pyrazinamide; Random Allocation; Tuberculosis

Novel extended side chain nitroimidazooxazine analogues featuring diverse linker groups between two aryl rings were studied as a potential strategy to improve solubility and oral activity against chronic infection by Mycobacterium tuberculosis. Both lipophilic and highly polar functionalities (e.g., carboxamide, alkylamine, piperazine, piperidine, but not sulfonamide) were well tolerated in vitro, and the hydrophilic linkers provided some solubility improvements, particularly in combination with pyridine rings. Most of the 18 compounds further assessed showed high microsomal stabilities, although in the acute infection mouse model, just one stilbene (6-fold) and two pyridine-containing acetylene derivatives (5-fold and >933-fold) gave in vivo efficacies notably superior to the clinical stage compound pretomanid (PA-824). The most efficacious analogue also displayed outstanding in vivo activity in the stringent chronic model (up to 24-fold better than the drug delamanid and 4-fold greater than our previous best phenylpyridine candidate), with favorable pharmacokinetics, including good oral bioavailability in the rat.

Topics: Administration, Oral; Animals; Antitubercular Agents; Biological Availability; Chemistry Techniques, Synthetic; Chronic Disease; Disease Models, Animal; Humans; Male; Mice, Inbred BALB C; Mice, Inbred Strains; Microbial Sensitivity Tests; Microsomes, Liver; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Rats, Sprague-Dawley; Structure-Activity Relationship; Tuberculosis

Bedaquiline (Sirturo) and delamanid (Deltyba) have recently been approved by the regulatory authorities for treatment of multidrug-resistant tuberculosis (MDR-TB). Antimicrobial susceptibility testing is not established for either substance. On the basis of the use of the MGIT 960 system equipped with EpiCenter/TB eXiST, we determined a mean bedaquiline MIC for wild-type strains of 0.65 mg/liter (median, 0.4 mg/liter) and an epidemiological cutoff (ECOFF) of 1.6 mg/liter; for delamanid, a mean wild-type drug MIC of 0.013 mg/liter (median, 0.01 mg/liter) and an ECOFF of 0.04 mg/liter were determined.

Topics: Antitubercular Agents; Diarylquinolines; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Reference Values; Tuberculosis; Tuberculosis, Multidrug-Resistant

Topics: Antitubercular Agents; Clinical Trials as Topic; Diarylquinolines; Drug Approval; Drug Discovery; Global Health; Humans; Nitroimidazoles; Oxazoles; Research Support as Topic; Tuberculosis

New heterocyclic analogues of the potent biphenyl class derived from antitubercular drug PA-824 were prepared, aiming to improve aqueous solubility but maintain high metabolic stability and efficacy. The strategy involved replacement of one or both phenyl groups by pyridine, pyridazine, pyrazine, or pyrimidine, in order to reduce lipophilicity. For para-linked biaryls, hydrophilicities (ClogP) correlated with measured solubilities, but highly soluble bipyridine analogues displayed weak antitubercular activities. A terminal pyridine or proximal heterocycle allowed retention of potency and provided solubility improvements, particularly at low pH, with examples from the latter classes displaying the better in vivo efficacies, high metabolic stabilities, and excellent pharmacokinetics. Five such compounds were >100-fold better than the parent drug in a mouse model of acute Mycobacterium tuberculosis infection, and two orally bioavailable pyridine analogues (3-4-fold more soluble than the parent at low pH) were superior to antitubercular drug OPC-67683 in a chronic infection model.

Topics: Animals; Antitubercular Agents; Disease Models, Animal; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred BALB C; Nitroimidazoles; Oxazines; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Tuberculosis

Tuberculosis (TB) is still a leading cause of death worldwide. Almost a third of the world's population is infected with TB bacilli, and each year approximately 8 million people develop active TB and 2 million die as a result. Today's TB treatment, which dates back to the 1970s, is long and burdensome, requiring at least 6 mo of multidrug chemotherapy. The situation is further compounded by the emergence of multidrug-resistant TB (MDR-TB) and by the infection's lethal synergy with HIV/AIDS. Global health and philanthropic organizations are now pleading for new drug interventions that can address these unmet needs in TB treatment.. Here we report OPC-67683, a nitro-dihydro-imidazooxazole derivative that was screened to help combat the unmet needs in TB treatment. The compound is a mycolic acid biosynthesis inhibitor found to be free of mutagenicity and to possess highly potent activity against TB, including MDR-TB, as shown by its exceptionally low minimum inhibitory concentration (MIC) range of 0.006-0.024 microg/ml in vitro and highly effective therapeutic activity at low doses in vivo. Additionally, the results of the post-antibiotic effect of OPC-67683 on intracellular Mycobacterium tuberculosis showed the agent to be highly and dose-dependently active also against intracellular M. tuberculosis H37Rv after a 4-h pulsed exposure, and this activity at a concentration of 0.1 microg/ml was similar to that of the first-line drug rifampicin (RFP) at a concentration of 3 microg/ml. The combination of OPC-67683 with RFP and pyrazinamide (PZA) exhibited a remarkably quicker eradication (by at least 2 mo) of viable TB bacilli in the lung in comparison with the standard regimen consisting of RFP, isoniazid (INH), ethambutol (EB), and PZA. Furthermore, OPC-67683 was not affected by nor did it affect the activity of liver microsome enzymes, suggesting the possibility for OPC-67683 to be used in combination with drugs, including anti-retrovirals, that induce or are metabolized by cytochrome P450 enzymes.. We concluded that based on these properties OPC-67683 has the potential to be used as a TB drug to help combat the unmet needs in TB treatment.

Topics: Animals; Antitubercular Agents; Blood; Cell Line; Humans; In Vitro Techniques; Intracellular Membranes; Macrophages; Mammals; Mice; Microbial Sensitivity Tests; Microsomes, Liver; Mycobacterium; Mycobacterium bovis; Mycolic Acids; Nitroimidazoles; Oxazoles; Treatment Outcome; Tuberculosis

In an effort to develop potent new antituberculosis agents that would be effective against both drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis, we prepared a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles substituted at the 2-position with various phenoxymethyl groups and a methyl group and investigated the in vitro and in vivo activity of these compounds. Several of these derivatives showed potent in vitro and in vivo activity, and compound 19 (OPC-67683) in particular displayed excellent in vitro activity against both drug-susceptible and drug-resistant strains of M. tuberculosis H37Rv (MIC = 0.006 microg/mL) and dose-dependent and significant in vivo efficacy at lower oral doses than rifampicin in mouse models infected with M. tuberculosis Kurono. The synthesis and structure-activity relationships of these new compounds are presented.

Topics: Antitubercular Agents; Drug Resistance, Microbial; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxazoles; Rifampin; Structure-Activity Relationship; Tuberculosis