pbtz169 and Tuberculosis

Tuberculosis is the leading bacterial killer worldwide. 8-Nitro-4

Topics: Antitubercular Agents; Chemistry, Pharmaceutical; Humans; Mycobacterium tuberculosis; Structure-Activity Relationship; Thiazines; Tuberculosis

Over the past 2000 years, tuberculosis (TB) has claimed more lives than any other infectious disease. In 2020 alone, TB was responsible for 1.5 million deaths worldwide, comparable to the 1.8 million deaths caused by COVID-19. The World Health Organization has stated that new TB drugs must be developed to end this pandemic. After decades of neglect in this field, a renaissance era of TB drug discovery has arrived, in which many novel candidates have entered clinical trials. However, while hundreds of molecules are reported annually as promising anti-TB agents, very few successfully progress to clinical development. In this Perspective, we critically review those anti-TB compounds published in the last 6 years that demonstrate good

Topics: Antitubercular Agents; COVID-19 Drug Treatment; Drug Discovery; Humans; Mycobacterium tuberculosis; Tuberculosis

Decaprenyl-phosphoryl-ribose 2'-epimerase (DprE1) inhibitors are an innovative and futuristic orally active group of antituberculosis agents. A few DprE1 inhibitors are in the clinical trial for tuberculosis (TB), including macozinone. This review highlights the discovery, developmental status, clinical studies, patents, and prospects of macozinone (MCZ). The patent and non-patent literature search was done by entering keywords such as macozinone; MCZ; PBTZ169; PBTZ-169 in Pubmed, Espacenet, Patentscope, and the USPTO databases. However, data on Sci-Finder was searched using CAS registry number: 1377239-83-2. MCZ clinical trial studies were retrieved from the clinicaltrials.gov database using the exact keywords. The chemical structure of MCZ was disclosed in 2009. Accordingly, patents/patent applications published from 2009 to June 12, 2022, have been discussed herein. MCZ and MCZ hydrochloride salt patents were granted in 2014 and 2019, respectively, in the USA. The patent literature and the clinical trial studies suggest capsule, tablet, and suspension formulations of crystalline MCZ and its hydrochloride salt as the possible and prospective dosage forms to treat TB. Some combinations of MCZ with other drugs (chloroquine, telacebec, tafenoquine, TBI-166, and sanfetrinem) with improved anti-TB efficacy have been documented. Based on the literature covered in this review article on the clinical studies and patents applied/granted to MCZ, it can be inferred that MCZ seems to be a promising DprE1 inhibitor and could help to tackle the emerging dilemma of drug-resistant either as a monotherapy or in combination with additional anti-TB agents. Furthermore, the authors anticipate the development of new combinations, salts, and polymorphs of MCZ as anti-TB agents shortly. This review article might prove beneficial to the scientific community as it summarizes chemistry, pharmacology and provides an update on the clinical studies and patents/patent applications of one of the emerging anti-TB drugs in one place.

Topics: Antitubercular Agents; Drug Delivery Systems; Humans; Mycobacterium tuberculosis; Prospective Studies; Tuberculosis

Piperazine, is privileged six membered nitrogen containing heterocyclic ring also known as 1,4-Diazacyclohexane. Consequently, piperazine is a versatile medicinally important scaffold and is an essential core in numerous marketed drugs with diverse pharmacological activities. In recent years several potent molecules containing piperazine as an essential subunit of the structural frame have been reported, especially against Mycobacterium tuberculosis (MTB). Remarkably, a good number of these reported molecules also displayed potential activity against multidrug-resistant (MDR), and extremely drug-resistant (XDR) strains of MTB. In this review, we have made a concerted effort to retrace anti-mycobacterial compounds for the past five decades (1971-2019) specifically where piperazine has been used as a vital building block. This review will benefit medicinal chemists as it elaborates on the design, rationale and structure-activity relationship (SAR) of the reported potent piperazine based anti-TB molecules, which in turn will assist them in addressing the gaps, exploiting the reported strategies and developing safer, selective, and cost-effective anti-mycobacterial agents.

Topics: Animals; Antitubercular Agents; Drug Design; Drug Discovery; Humans; Mycobacterium tuberculosis; Piperazine; Structure-Activity Relationship; Tuberculosis

Despite enormous efforts have been made in the hunt for new drugs, tuberculosis (TB) still remains the first bacterial cause of mortality worldwide, causing an estimated 8.6 million new cases and 1.3 million deaths in 2012. Multi-drug resistant-TB strains no longer respond to first-line drugs and are inexorably spreading with an estimated 650,000 cases as well as extensively-drug resistant-TB strains, which are resistant to any fluoroquinolone and at least one of the second-line drugs, with 60,000 cases. Thus the discovery and development of new medicines is a major keystone for tuberculosis treatment and control. After decades of dormancy in the field of TB drug development, recent efforts from various groups have generated a promising TB drug pipeline. Several new therapeutic agents are concurrently studied in clinical trials together with much activity in the hittolead and lead optimization stages. In this article we will review the recent advances in TB drug discovery with a special focus on structure activity relationship studies of the most advanced compound classes.

Topics: Animals; Antitubercular Agents; Humans; Mycobacterium tuberculosis; Structure-Activity Relationship; Tuberculosis; Tuberculosis, Multidrug-Resistant

Tuberculosis, and especially multidrug-resistant tuberculosis (MDR-TB), is a major global health threat which emphasizes the need to develop new agents to improve and shorten treatment of this difficult-to-manage infectious disease. Among the new agents, macozinone (PBTZ169) is one of the most promising candidates, showing extraordinary potency in vitro and in murine models against drug-susceptible and drug-resistant Mycobacterium tuberculosis. A previous analytical method using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was developed by our group to support phase I clinical trials of PBTZ169. These plasma sample analyses revealed the presence of several additional metabolites among which the most prominent was H

Topics: Animals; Chromatography, Liquid; Clinical Trials, Phase I as Topic; Humans; Mammals; Mice; Piperazines; Reproducibility of Results; Tandem Mass Spectrometry; Tuberculosis; Tuberculosis, Multidrug-Resistant

Tuberculosis (TB) is the leading cause of death from any bacterial infection, causing 1.5 million deaths worldwide each year. Due to the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb) there have been significant efforts aimed at developing novel drugs to treat TB. One promising drug target in Mtb is the arabinogalactan biosynthetic enzyme DprE1, and there have been over a dozen unique chemical scaffolds identified which inhibit the activity of this protein. Among the most promising lead compounds are the benzothiazinones BTZ043 and PBTZ169, both of which are currently in or have completed phase IIa clinical trials. Due to the potential clinical utility of these drugs, we sought to identify potential synergistic interactions and new mechanisms of resistance using a genome-scale CRISPRi chemical-genetic screen with PBTZ169. We found that knockdown of

Topics: Antitubercular Agents; Diarylquinolines; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Piperazines; Spiro Compounds; Thiazines; Tuberculosis; Tuberculosis, Multidrug-Resistant

Q203 is a first-in-class drug candidate against Mycobacterium tuberculosis. In its recently completed phase 2 clinical trial, Q203 reduced the number of live M. tuberculosis cells in a dose-dependent manner. This orally active small molecule blocks M. tuberculosis growth by inhibiting the cytochrome

Topics: Animals; Antitubercular Agents; Mycobacterium tuberculosis; Tuberculosis; Zebrafish

Multiple drug discovery initiatives for tuberculosis are currently ongoing to identify and develop new potent drugs with novel targets in order to shorten treatment duration. One of the drug classes with a new mode of action is DprE1 inhibitors targeting an essential process in cell wall synthesis of Mycobacterium tuberculosis. In this investigation, three DprE1 inhibitors currently in clinical trials, TBA-7371, PBTZ169, and OPC-167832, were evaluated side-by-side as single agents in the C3HeB/FeJ mouse model presenting with caseous necrotic pulmonary lesions upon tuberculosis infection. The goal was to confirm the efficacy of the DprE1 inhibitors in a mouse tuberculosis model with advanced pulmonary pathology and perform comprehensive analysis of plasma, lung, and lesion-centric drug levels to establish pharmacokinetic-pharmacodynamic (PK-PD) parameters predicting efficacy at the site of infection. Results showed significant efficacy for all three DprE1 inhibitors in the C3HeB/FeJ mouse model after 2 months of treatment. Superior efficacy was observed for OPC-167832 even at low-dose levels, which can be attributed to its low MIC, favorable distribution, and sustained retention above the MIC throughout the dosing interval in caseous necrotic lesions, where the majority of bacteria reside in C3HeB/FeJ mice. These results support further progression of the three drug candidates through clinical development for tuberculosis treatment.

Topics: Animals; Mice; Mice, Inbred C3H; Mycobacterium tuberculosis; Piperazines; Thiazines; Tuberculosis

Tuberculosis is a chronic infectious disease, usually localized in the respiratory system and representing one of the most important global social and biomedical health problems associated with the spread of therapy-resistant forms (multidrug-resistant and extensively drug-resistant tuberculosis). One of the most promising targets for the development of antimycobacterial drugs is the enzyme DprE1, which is involved in the synthesis of the cell wall of mycobacteria. In the series of DprE1 inhibitor drugs, the most advanced drug is PBTZ169 (INN maсozinone). Clinical trials (CT) of the efficacy and safety of macozinone are conducted by the pharmaceutical company LLC NEARMEDIC PLUS in the Russian Federation, and in other countries (Sponsors: Innovative Medicines for Tuberculosis Foundation, cole polytechnique fdrale de Lausanne and Bill and Melinda Gates Foundation). The publication describes results of completed I, IIa and Ib phases CT, conducted in the Russian Federation.. The goal of phase I CT was to assess the safety, tolerability and pharmacokinetics (PK) of PBTZ169, 40 mg capsule, after single and multiple administration under fasting conditions in increasing doses in healthy volunteers. The goal of phase IIa CT was to study the efficacy (in terms of early bactericidal activity EBA), safety and PK of the drug PBTZ169, 80 mg capsules, in various doses, when used as monotherapy in patients with newly diagnosed respiratory tuberculosis with bacterial excretion and retained sensitivity to isoniazid and rifampicin. The purpose of phase Ib CT was to evaluate the safety, tolerability, PK of PBTZ169, 80 mg capsule, after single, double and multiple administration under fasting conditions in increasing doses, as well as the effect of food on its bioavailability in healthy volunteers.. The data of 100 healthy volunteers and 15 patients with newly diagnosed pulmonary tuberculosis, who received the study medication PBTZ169, capsules 40 mg and 80 mg, in the dose range 40 mg 1280 mg of PBTZ169, obtained during phase I, IIa and Ib CTs were analyzed. During I phases CTs, safety, tolerability, and PK of the drug after a single and multiple administration under fasting condition and after meals at rising doses were evaluated. The safety assessment included evaluation of AE/SAE, vital signs, ECG results, and laboratory tests results in the safety population. In the course of phase IIa CT, in addition to safety, tolerance, and PK evaluation, the efficacy of the drug (in terms of EBA) using sputum culture on agar with CFU/ml counting (main method) and quantitative PCR method (auxiliary method) was evaluated.. During all CTs, a high safety and tolerability profile was shown, the main PK parameters of the drug and the efficacy were described. PBTZ169 demonstrated linear PK in the dosage range up to 640 mg after single and multiple administration, a statistically significant of EBA of the drug after monotherapy at the dose of 640 mg/day was demonstrate, and it was concluded that the preferred regimen of the drug PBTZ169 intake is administration after meals. Good tolerability and a favorable safety profile of the drug in the studied doses range were demonstrate during all the CTs.. One of the most promising and currently studied drugs-inhibitors of DprE1, a new target for the cell wall of mycobacteria, is PBTZ169 or macozinone, which is being develop by the Russian pharmaceutical company NEARMEDIC PLUS ltd.. Туберкулез хроническое инфекционное заболевание, как правило, локализующееся в органах дыхания и представляющее одну из важнейших глобальных социальных и медико-биологических проблем здравоохранения, связанную с распространением устойчивых к терапии форм (туберкулез с множественной и широкой лекарственной устойчивостью). Одной из наиболее перспективных мишеней для разработки антимикотических лекарственных препаратов является фермент DprE1, участвующий в синтезе клеточной стенки микобактерий. В ряду препаратов ингибиторов DprE1 наиболее изучен препарат PBTZ169 (международное непатентованное наименование макозинон), клинические исследования (КИ) эффективности и безопасности которого проводились как на территории Российской Федерации (спонсор ООО НИАРМЕДИК ПЛЮС), так и за рубежом (спонсоры Фонд Innovative Medicines for Tuberculosis, cole polytechnique fdrale de Lausanne и Bill and Melinda Gates Foundation). В публикации описаны результаты завершенных КИ I, IIа и Ib фаз, проведенных на территории Российской Федерации. Цель. Цель I фазы КИ заключалась в оценке безопасности, переносимости и фармакокинетики препарата PBTZ169, капсулы 40 мг, после однократного и многократного применения натощак в возрастающих дозах у здоровых добровольцев. Цель IIа фазы КИ заключалась в изучении эффективности (по параметру ранней бактерицидной активности РБА), безопасности и фармакокинетики препарата PBTZ169, капсулы 80 мг, в разных дозах при применении в качестве монотерапии у пациентов с впервые выявленным туберкулезом органов дыхания с бактериовыделением и сохраненной чувствительностью к изониазиду и рифампицину. Цель Ib фазы КИ заключалась в оценке безопасности, переносимости, фармакокинетики препарата PBTZ169, капсулы 80 мг, при однократном, двукратном и многократном применении натощак в возрастающих дозах, а также влияния пищи на его биодоступность у здоровых добровольцев. Материалы и методы. Проанализированы данные, полученные в результате I, IIа и Ib фаз КИ PBTZ169, в ходе которых 100 здоровых добровольцев и 15 пациентов с впервые выявленным туберкулезом легких принимали исследуемый препарат PBTZ169, капсулы 40 и 80 мг, в диапазоне доз от 40 до 1280 мг. В ходе КИ I фазы изучались безопасность, переносимость и фармакокинетика применяемых доз натощак и после еды при однократном и многократном применении. Оценка безопасности включала определение нежелательных явлений/серьезных нежелательных явлений, жизненно важных функций, данных электрокардиографии и лабораторных анализов

Topics: Antitubercular Agents; Humans; Pharmaceutical Preparations; Piperazines; Russia; Thiazines; Tuberculosis

A piperazine-containing benzothiazinones lead compound PBTZ169, served as DprE1 inhibitor, displays nanomolar bactericidal activity against Mycobacteria tuberculosis. Here, we systematically evaluate anti-tuberculosis activity of one of PBTZ169 analogues, TZY-5-84, in vitro and in vivo. The MIC value of TZY-5-84 against M. tuberculosis H37Rv ranged from 0.014 to 0.015 mg/L, lower than those of INH, RFP and BDQ. Five susceptible and thirteen drug-resistant clinical isolates were also susceptive to TZY-5-84. It had anti-tuberculosis activity against intracellular bacilli in infected macrophage model. It exhibited its activity in time-dependent manner and against intracellular bacilli in infected macrophage cells. However, the MIC of TZY-5-84 against three laboratory PBTZ169-induced resistant isolates increased four-fold increment compared to that of H37Rv. No antagonism was observed in any combination between TZY-5-84 and seven commonly used anti-tuberculosis drugs in an in vitro checkerboard assay. In murine infection model, TZY-5-84 at lower dosage (12.5 mg/kg) was found to be comparatively efficacious as PBTZ169 at 25 mg/kg. Our research suggests TZY-5-84 can be a promising preclinical candidate for further study on TB treatment.

Topics: Animals; Antitubercular Agents; Dose-Response Relationship, Drug; Female; Macrophages; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Piperazine; Piperazines; Thiazines; Time Factors; Tuberculosis; Tuberculosis, Multidrug-Resistant

A series of benzothiazinones (BTZs) containing an oxime moiety, based on the structure of ZR-10 discovered in our lab, were designed and synthesized. Most of the compounds with alkoxyimino groups attached to the piperazine or cyclohexyl ring of PBTZ169, exhibit excellent in vitro activity against both drug-sensitive and clinically isolated multidrug-resistant Mycobacterium tuberculosis (MTB) strains (MIC: < 0.016-0.037 μg/mL) and low cell cytotoxicity. Two close PBTZ169-analogues 3a and 3b with proper ADME/T and PK properties show potent in vivo efficacy in an acute mouse model of tuberculosis. Compound 3a is under evaluation as a potential clinical candidate for treatment of tuberculosis.

Topics: Animals; Antitubercular Agents; Drug Design; Female; Humans; Mice, Inbred ICR; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oximes; Piperazines; Thiazines; Tuberculosis

We herein report the design and synthesis of benzothiazinones containing a piperidine moiety as new antitubercular agents based on the structure feature of IMB-ZR-1 discovered in our lab. Some of them were found to have good in vitro activity (MIC < 1 μg/mL) against drug-susceptible Mycobacterium tuberculosis H37RV strain. After two set of modifications, compound 2i were found to display comparable in vitro anti-TB activity (MIC < 0.016 μg/mL) to PBTZ169 against drug-sensitive and resistant mycobacterium tuberculosis strains. Compound 2i also showed acceptable PK profiles. Studies to determine PK profiles in lung and in vivo efficacy of 2i are currently under way.

Topics: Animals; Antitubercular Agents; Drug Design; Female; Humans; Mice, Inbred ICR; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Piperidines; Thiazines; Tuberculosis

Tuberculosis (TB) remains a major human health problem. New therapeutic antitubercular agents are urgent needed to control the global tuberculosis pandemic. We synthesized a new series of 4-carbonyl piperazine substituted 1,3-benzothiazin-4-one derivatives and evaluated their anti-mycobacterial activities against Mycobacterium tuberculosis H37Ra as well as their druggabilities. The results showed that most of these derivatives, especially the compounds with simple alkyl side chains, exhibited good antitubercular activities and favorable aqueous solubilities with no obvious cytotoxicity. It suggested that the 4-carbonyl piperazine substituents in benzothiazinone scaffold were well tolerated, in which the compound 8h, with an antitubercular activity of MIC 0.008 μM, exhibited an excellent aqueous solubility of 104 μg/mL, which was 100-fold better than the potent DprE1 inhibitor Comp.1 (BTZ038), also more soluble than PBTZ169.

Topics: Animals; Antitubercular Agents; Chlorocebus aethiops; Dose-Response Relationship, Drug; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Piperazine; Piperazines; Structure-Activity Relationship; Thiazines; Tuberculosis; Vero Cells

8-Nitro-benzothiazinones (BTZs), such as BTZ043 and PBTZ169, inhibit decaprenylphosphoryl-β-d-ribose 2'-oxidase (DprE1) and display nanomolar bactericidal activity against Mycobacterium tuberculosis in vitro. Structure-activity relationship (SAR) studies revealed the 8-nitro group of the BTZ scaffold to be crucial for the mechanism of action, which involves formation of a semimercaptal bond with Cys387 in the active site of DprE1. To date, substitution of the 8-nitro group has led to extensive loss of antimycobacterial activity. Here, we report the synthesis and characterization of the pyrrole-benzothiazinones PyrBTZ01 and PyrBTZ02, non-nitro-benzothiazinones that retain significant antimycobacterial activity, with MICs of 0.16 μg/ml against M. tuberculosis. These compounds inhibit DprE1 with 50% inhibitory concentration (IC50) values of <8 μM and present favorable in vitro absorption-distribution-metabolism-excretion/toxicity (ADME/T) and in vivo pharmacokinetic profiles. The most promising compound, PyrBTZ01, did not show efficacy in a mouse model of acute tuberculosis, suggesting that BTZ-mediated killing through DprE1 inhibition requires a combination of both covalent bond formation and compound potency.

Topics: Alcohol Oxidoreductases; Animals; Antitubercular Agents; Bacterial Proteins; Catalytic Domain; Disease Models, Animal; Hep G2 Cells; Humans; Male; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Piperazines; Pyridines; Pyrroles; Spiro Compounds; Structure-Activity Relationship; Thiazines; Tuberculosis

The benzothiazinone lead compound, BTZ043, kills Mycobacterium tuberculosis by inhibiting the essential flavo-enzyme DprE1, decaprenylphosphoryl-beta-D-ribose 2-epimerase. Here, we synthesized a new series of piperazine-containing benzothiazinones (PBTZ) and show that, like BTZ043, the preclinical candidate PBTZ169 binds covalently to DprE1. The crystal structure of the DprE1-PBTZ169 complex reveals formation of a semimercaptal adduct with Cys387 in the active site and explains the irreversible inactivation of the enzyme. Compared to BTZ043, PBTZ169 has improved potency, safety and efficacy in zebrafish and mouse models of tuberculosis (TB). When combined with other TB drugs, PBTZ169 showed additive activity against M. tuberculosis in vitro except with bedaquiline (BDQ) where synergy was observed. A new regimen comprising PBTZ169, BDQ and pyrazinamide was found to be more efficacious than the standard three drug treatment in a murine model of chronic disease. PBTZ169 is thus an attractive drug candidate to treat TB in humans.

Topics: Alcohol Oxidoreductases; Animals; Antitubercular Agents; Bacterial Proteins; Binding Sites; Catalytic Domain; Crystallography, X-Ray; Disease Models, Animal; Embryo, Nonmammalian; Hep G2 Cells; Humans; Lung; Mice; Molecular Dynamics Simulation; Mycobacterium tuberculosis; Piperazines; Spiro Compounds; Spleen; Thiazines; Tuberculosis; Zebrafish