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- | Journal: Verapamil and its metabolite norverapamil inhibit the Mycobacterium tuberculosis MmpS5L5 efflux pump to increase bedaquiline activity. (Pubmed Central) - Apr 17, 2025
Here, we show that the MmpS5L5 efflux pump reduces susceptibility to bedaquiline as well as its new, more potent derivative TBAJ-876 and other antimicrobial substrates, including clofazimine and the DprE1 inhibitors PBTZ-169 and OPC-167832...Finally, norverapamil, the major verapamil metabolite, which has greatly reduced calcium channel activity, has equal potency in reducing resistance to MmpS5L5 substrates. Our findings highlight verapamil's potential for enhancing bedaquiline TB treatment, for preventing acquired resistance to bedaquiline and other MmpS5L5 substrates, while also providing the impetus to identify additional MmpS5L5 inhibitors.
- | Journal: Bibliometric and Visualization Analysis of DprE1 Inhibitors to Combat Tuberculosis. (Pubmed Central) - Apr 8, 2025
These results can serve as a data-driven reference for future research and offer precise insights into the development of anti-TB agents associated with DprE1. To the best of our knowledge, this study is the first to comprehensively investigate DprE1 in TB by means of bibliometric analysis.
- | Journal: Discovery of novel pyrimidinetrione derivatives as DprE1 inhibitors with potent antimycobacterial activities. (Pubmed Central) - Mar 27, 2025
In addition, the binding affinity of compound 42 is equivalent to that of G50. This study further enriches the examples of developing DprE1 inhibitors based on the backbone of pyrimidinetrione and also provides potential anti-tuberculosis lead compounds.
- Minimum inhibitory concentrations of quabodepistat in Mycobacterium tuberculosis clinical isolates from patients with drug-susceptible pulmonary tuberculosis (Hall 13) - Mar 4, 2025 - Abstract #ESCMIDGlobal2025ESCMID_Global_6655;
- | rifampicin / Generic mfg.
Preclinical, Journal: Preclinical Evaluation of Selene-Ethylenelacticamides in Tuberculosis: Effects Against Active, Dormant, and Resistant Mycobacterium Tuberculosis and In Vitro Toxicity Investigation. (Pubmed Central) - Feb 26, 2025
Molecular docking simulations were used to evaluate Mycobacterium tuberculosis DprE1 and dihydrofolate reductase enzymes as putative targets of selene-ethylenelacticamides, mechanisms that could contribute to the antitubercular activity. Our findings reveal that NC34 may represent a hit for further drug optimization and for future preclinical development as a new anti-mycobacterial agent, especially in cases of resistant and/or dormant forms of tuberculosis.
- | Journal: 3D-QSAR and ADMET studies of morpholino-pyrimidine inhibitors of DprE1 from Mycobacterium tuberculosis. (Pubmed Central) - Feb 18, 2025
Highly active compounds 47, 49 and 50 of MP series exhibited highly favourable drug-like properties. SAR and ADMET insights attained from this model will help in the development of active DprE1 inhibitors in future.Communicated by Ramaswamy H. Sarma.
- || P1/2 data, PK/PD data, Journal: Safety, bactericidal activity, and pharmacokinetics of the antituberculosis drug candidate BTZ-043 in South Africa (PanACEA-BTZ-043-02): an open-label, dose-expansion, randomised, controlled, phase 1b/2a trial. (Pubmed Central) - Feb 9, 2025
P1/2
Based on a small sample size, BTZ-043 is a promising antituberculosis drug candidate with favourable safety and good bactericidal activity. Larger follow-up studies are needed to detect any less frequent safety signals, further explore drug-drug interactions, identify the best dose, and evaluate efficacy in combination with other drugs.
- Nanomotion Technology for Rapid Antimicrobial Susceptibility Testing of Mycobacterium tuberculosis: Evaluating Novel Benzothiazinone Derivatives. (Hall 5) - Feb 1, 2025 - Abstract #ESCMIDGlobal2025ESCMID_Global_759;
- | macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation
Journal: Real-time evaluation of macozinone activity against Mycobacterium tuberculosis through bacterial nanomotion analysis. (Pubmed Central) - Jan 31, 2025
PBTZ169 and H2-PBTZ169 achieved 100% separation between the susceptible H37Rv and a resistant dprE1 mutant strain NTB1. These findings support nanomotion technology's potential for faster antibiotic susceptibility testing of novel MTB drug candidates targeting the DprE1 enzyme that could reduce empirical treatment duration and antibiotic resistance selection pressure due to inaccurate treatments.
- | Journal: Structure-based drug design and characterization of novel pyrazine hydrazinylidene derivatives with a benzenesulfonate scaffold as noncovalent inhibitors of DprE1 tor tuberculosis treatment. (Pubmed Central) - Dec 20, 2024
To deepen our understanding of these compounds, we have undertaken an in silico analysis encompassing Absorption, Distribution, Metabolism, and Excretion (ADME) considerations. Furthermore, molecular docking analyses against the DprE1 enzyme was conducted and Density-Functional Theory (DFT) studies were employed to elucidate the electronic properties of the compounds, thereby enhancing our understanding of their pharmacological potential.
- | macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation
Preclinical, Journal: Efficacy of Macozinone in Mice with Genetically Diverse Susceptibility to Mycobacterium tuberculosis Infection. (Pubmed Central) - Dec 1, 2024
Macozinone demonstrated efficacy to varying degrees across all mouse models of Mtb infection used. These results should facilitate its further development and potential introduction into clinical practice.
- | macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation
Journal: Benzothiazinone analogs as Anti-Mycobacterium tuberculosis DprE1 irreversible inhibitors: Covalent docking, validation, and molecular dynamics simulations. (Pubmed Central) - Nov 25, 2024
Macozinone (PBTZ169, a benzothiazinone (BTZ) derivative) is an irreversible DprE1 inhibitor that has attracted considerable attention because it exhibits an additive activity when combined with other anti-TB drugs...Physicochemical and ADMET characteristics indicated the oral bioavailability of the identified BTZ analogs. The obtained in-silico results provide promising anti-TB inhibitors that are worth being subjected to in-vitro and in-vivo investigations.
- | Preclinical, Journal: Noncovalent inhibitors of DprE1 for tuberculosis treatment: design, synthesis, characterization, in (Pubmed Central) - Nov 17, 2024
Additionally, molecular docking analyses were executed to elucidate their interactions with the DprE1 enzyme. Finally, Density Functional Theory studies were leveraged to explore the electronic characteristics of these compounds, thereby providing insights into their potential utility in the realm of pharmaceuticals.
- | Journal: Replacement of the essential nitro group by electrophilic warheads towards nitro-free antimycobacterial benzothiazinones. (Pubmed Central) - Oct 27, 2024
Herein, we synthesized and characterized various covalent warheads covering different reaction principles. Covalent inhibition was confirmed for most active antimycobacterial compounds by enzymatic inhibition assays and peptide fragment analysis.
- | Journal: Design, synthesis and antimycobacterial activity of novel benzothiazinones with improved water solubility. (Pubmed Central) - Oct 27, 2024
Here, we designed and synthesized a series of new BTZ derivatives, wherein a hydrophilic COOH or NH2 group is directly attached to the oxime moiety of TZY-5-84 discovered in our lab, through various linkers. Two compounds 1a and 3 were first reported to possess excellent activity against MTB H37Rv and MDR-MTB strains (MIC:
- | Journal: 3,5-disubstituted pyridines with potent activity against drug-resistant Mycobacterium tuberculosis clinical isolates. (Pubmed Central) - Oct 4, 2024
Importantly, compound 24 showed a selectivity index of 54.64 against CHO-K1 and 78.26 against VERO cell lines, while compound 26 showed a selectivity index of 108.5 against CHO-K1 and 63.2 against VERO cell lines, respectively. Compound 24 formed a stable complex with the target protein DprE1 with predicted binding energy -8.73
- | Journal: Novel hybrids of 1,2,3-triazole-benzoxazole: design, synthesis, and assessment of DprE1 enzyme inhibitors using fluorometric assay and computational analysis. (Pubmed Central) - Sep 27, 2024
Through molecular modelling and dynamic simulations, we explored the structural relationships between selected 1,2,3-triazole compounds and DprE1, revealing key features for effective drug-target interactions. This study introduces a novel approach for designing ligands against DprE1, offering a potential therapeutic strategy for tuberculosis treatment.
- | Journal: Development and Evaluation of Bis-benzothiazoles as a New Class of Benzothiazoles Targeting DprE1 as Antitubercular Agents. (Pubmed Central) - Sep 15, 2024
SNPs in dprE-1 gene assessment revealed that compound 6a binds to tyrosine at position 314 of DprE1 and replaces it with histidine, causing resistance similar to that of standard TCA1. In silico docking studies further suggest that the strong noncovalent interactions of these compounds may lead to the development of potent noncovalent DprE1 inhibitors.
- | Journal: Pharmacophore mapping, 3D QSAR, molecular docking, and ADME prediction studies of novel Benzothiazinone derivatives. (Pubmed Central) - Sep 2, 2024
Docking validation via RMSD values supported the reliability of the docking results. This comprehensive approach aids in the design of novel benzothiazinone derivatives with potential anti-tubercular properties, contributing to the development of novel anti-tubercular agents which can be pivotal in the eradication of tuberculosis.
- || recombinant exendin-4 (Uni-E4) - Uni / Bio Sci
Review, Journal: Candidate anti-tuberculosis medicines and regimens under clinical evaluation. (Pubmed Central) - Aug 15, 2024
This comprehensive approach aids in the design of novel benzothiazinone derivatives with potential anti-tubercular properties, contributing to the development of novel anti-tubercular agents which can be pivotal in the eradication of tuberculosis. A large number of potential anti-TB candidate medicines and innovations in clinical trial design for the evaluation of regimens, rather than single medicines, provide hope for improvements in the treatment of TB.
- | Journal: DprE1 and Ddn as promising therapeutic targets in the development of novel anti-tuberculosis nitroaromatic drugs. (Pubmed Central) - Jun 16, 2024
Despite renewed interest in the development of new anti-tuberculosis nitroaromatic compounds, pharmaceutical companies often exclude nitro-containing molecules from their drug discovery programs because of their toxic and mutagenic potential. This exclusion results in missed opportunities to identify new nitroaromatic compounds and promising therapeutic targets.
- | Journal: Targeting decaprenylphosphoryl-?-D-ribose 2'-epimerase for Innovative Drug Development Against Mycobacterium Tuberculosis Drug-Resistant Strains. (Pubmed Central) - May 30, 2024
Integrated computational and pharmacophore methodologies offer valuable insights into drug candidates and their interactions within intricate protein environments. This research lays a strategic foundation for targeted interventions against drug-resistant TB, highlighting ligand 2's potential for advanced drug development strategies.
- || Review, Journal: Recent advances in the development of DprE1 inhibitors using AI/CADD approaches. (Pubmed Central) - May 26, 2024
Recent studies have shown that artificial intelligence/computer-aided drug design (AI/CADD) techniques are powerful tools in the discovery of novel DprE1 inhibitors. This review provides an overview of the discovery of DprE1 inhibitors and their underlying mechanism of action and highlights recent advances in the discovery and optimization of DprE1 inhibitors using AI/CADD approaches.
- | Preclinical, Journal: Design, Synthesis and In vitro Antitubercular Effect of New Chalcone Derivatives Coupled with 1,2,3-Triazoles: A Computational Docking Techniques. (Pubmed Central) - May 15, 2024
This review provides an overview of the discovery of DprE1 inhibitors and their underlying mechanism of action and highlights recent advances in the discovery and optimization of DprE1 inhibitors using AI/CADD approaches. Based on docking results, 8d showed that the amino acids His74(A), Lys76(A), Cys332(A), Asp331(A), Val307(A), Tyr357(A), ect.,
- | Preclinical, Journal: Bactericidal and sterilizing activity of novel regimens combining bedaquiline or TBAJ-587 with GSK2556286 and TBA-7371 in a mouse model of tuberculosis. (Pubmed Central) - Apr 4, 2024
In addition, we found that GSK2556286 and TBA-7371 were as effective as pretomanid and the novel oxazolidinone TBI-223 when either drug pair was combined with TBAJ-587 and that the addition of GSK2556286 increased the bactericidal activity of the TBAJ-587, pretomanid, and TBI-223 combination. We conclude that GSK2556286 and TBA-7371 have the potential to replace pretomanid, an oxazolidinone, or both components, in combination with bedaquiline or TBAJ-587.
- A 4-Month Regimen of Quabodepistat, Delamanid, and Bedaquiline for Pulmonary TB: Interim Results () - Mar 16, 2024 - Abstract #CROI2024CROI_1211;
P2
In this interim analysis, high rates of SCC were achieved with the QBS-based three-drug treatment regimen. The regimen was generally well tolerated and warrants further investigation.
- Computational investigation of novel multi-targeted anti-tubercular agents by combined atom-based 3D-QSAR analysis, molecular docking, ADME-Tox, MD simulation and density functional theory (DFT) approaches (Virtual; Virtual Session (Virtual Only)) - Mar 12, 2024 - Abstract #ACSSp2024ACS_Sp_11459;
The result of highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) and energy gap analysis predicts the molecular reactivity and stability of identified molecule. Based on the result of the above studies the proposed compound can be successfully used towards the development of novel multi targeted anti-tubercular agent with high binding affinity and favourable ADME-T properties.
- | Journal: N-Substituted piperazine-coupled imidazo[2,1-b]thiazoles as inhibitors of Mycobacterium tuberculosis: Synthesis, evaluation, and docking studies. (Pubmed Central) - Feb 13, 2024
Based on the result of the above studies the proposed compound can be successfully used towards the development of novel multi targeted anti-tubercular agent with high binding affinity and favourable ADME-T properties. In vitro screening of new derivatives against Mycobacterium tuberculosis H37Rv
- || Clinical protocol, P2b data, Journal, Combination therapy: Quabodepistat in combination with delamanid and bedaquiline in participants with drug-susceptible pulmonary tuberculosis: protocol for a multicenter, phase 2b/c, open-label, randomized, dose-finding trial to evaluate safety and efficacy. (Pubmed Central) - Jan 24, 2024
P2
QBS's potent bactericidal activity and distinct mechanism of action (compared with other TB drugs currently available for human use) may make it an ideal candidate for inclusion in a novel treatment regimen to improve efficacy and potentially prevent resistance to concomitant TB drugs. This trial will assess the effectiveness, safety, and dosing of a new, shorter, QBS-based, combination anti-TB treatment regimen.
- | fluconazole oral / Generic mfg.
Preclinical, Journal: New thiazolyl-isoxazole derivatives as potential anti-infective agents: design, synthesis, in (Pubmed Central) - Jan 23, 2024
Compounds 9c-e, 9g-j, and 9q-t showed comparable activity concerning the reference drug fluconazole...The compound 9r was evaluated for structural dynamics and molecular dynamics simulations. The potent antitubercular and antimicrobial activity of 5-aryl-3-(2-arylthiazol-4-yl)isoxazole (9a-t) derivatives has recommended that these compounds could assist in treating microbial infections.Communicated by Ramaswamy H. Sarma.
- | TBA-7371 / Bill & Melinda Gates Foundation, Global Alliance for TB Drug Development, Foundation for Neglected Disease Research
Journal: Discovery of N-(1-(6-Oxo-1,6-dihydropyrimidine)-pyrazole) Acetamide Derivatives as Novel Noncovalent DprE1 Inhibitors against Mycobacterium tuberculosis. (Pubmed Central) - Jan 17, 2024
LK-60 is also the most active DprE1 inhibitor derived from CADD so far. Further studies confirmed their high affinity to DprE1, good safety profiles to gut microbiota and human cells, and synergy effects with either rifampicin or ethambutol, indicating their broad potential for clinical applications.
- | Journal: Both Nitro Groups Are Essential for High Antitubercular Activity of 3,5-Dinitrobenzylsulfanyl Tetrazoles and 1,3,4-Oxadiazoles through the Deazaflavin-Dependent Nitroreductase Activation Pathway. (Pubmed Central) - Jan 2, 2024
However, these analogues also showed increased toxicity to the mammalian cell line. Thus, both nitro groups in 3,5-dinitrobenzylsulfanyl-containing antimycobacterial agents remain essential for their high efficacy, and further efforts should be directed at finding ways to address the possible toxicity and solubility issues, for example, by targeted delivery.
- | Preclinical, Journal: Drug distribution and efficacy of the DprE1 inhibitor BTZ-043 in the C3HeB/FeJ mouse tuberculosis model. (Pubmed Central) - Dec 17, 2023
BTZ-043 treatment was associated with improved histology scores of pulmonary lesions, especially compared to control mice, which experienced advanced fulminant neutrophilic alveolitis in the absence of treatment. These positive treatment responses to BTZ-043 monotherapy in a mouse model of advanced pulmonary disease can be attributed to favorable distribution in tissues and lesions, retention in the caseum, and its high potency and bactericidal nature at drug concentrations achieved in necrotic lesions.
- || PK/PD data, Preclinical, Journal: Novel indolinone-tethered benzothiophenes as anti-tubercular agents against MDR/XDR M. tuberculosis: Design, synthesis, biological evaluation and in vivo pharmacokinetic study. (Pubmed Central) - Dec 10, 2023
For further exploration of the anti-tubercular mechanism of action, molecular docking was carried out for the former compound in DprE1 active site as one of the important biological targets of TB. The binding mode and the docking score uncovered exceptional binding when compared to the co-crystallized ligand suggesting that it maybe the underlying target for its outstanding anti-tubercular potency.
- | ciprofloxacin oral / Generic mfg., ethambutol / Generic mfg.
Journal: Design, synthesis and antitubercular assessment of 1, 2, 3-triazole incorporated thiazolylcarboxylate derivatives. (Pubmed Central) - Nov 19, 2023
The binding mode and the docking score uncovered exceptional binding when compared to the co-crystallized ligand suggesting that it maybe the underlying target for its outstanding anti-tubercular potency. The two compounds 7?h and 8?h have displayed excellent antitubercular activity with MIC values of 3.12 and 1.56?
- | Journal: Novel antitubercular agents: Design, synthesis, molecular dynamic and biological studies of pyrazole - 1,2,4-triazole conjugates. (Pubmed Central) - Oct 26, 2023
The two compounds 7?h and 8?h have displayed excellent antitubercular activity with MIC values of 3.12 and 1.56? An in-vitro cytotoxicity study on normal cell lines (MCF10) revealed safe compounds (IC50 values:341.85 to 726.08
- || Review, Journal: An insight into the discovery, clinical studies, compositions, and patents of macozinone: A drug targeting the DprE1 enzyme of Mycobacterium tuberculosis. (Pubmed Central) - Oct 22, 2023
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.
- | Journal: Selection of Multi-Drug Targets against Drug-Resistant Mycobacterium tuberculosis XDR1219 Using the Hyperbolic Mapping of the Protein Interaction Network. (Pubmed Central) - Sep 28, 2023
Our approach provides mechanistic explanations for existing drugs and suggests new DTs. This strategy can also be applied to the study of other resistant strains.
- | Journal: Synthesis and Structure-Activity Relationships of a New Class of Oxadiazoles Targeting DprE1 as Antitubercular Agents. (Pubmed Central) - Sep 22, 2023
Whole genome sequencing of genomic DNA from resistant mutants raised to P1 revealed mutations in decaprenylphosphoryl-?-d-ribose 2'-oxidase (DprE1). This novel oxadiazole scaffold expands the set of chemical tools for targeting a well-validated pathway to treat tuberculosis.
- | pretomanid (PA-824) / Global Alliance for TB Drug Development
Preclinical, Journal: Discovery and characterization of antimycobacterial nitro-containing compounds with distinct mechanisms of action and in vivo efficacy. (Pubmed Central) - Sep 20, 2023
Unlike pretomanid which depends only on deazaflavin-dependent nitroreductase (Ddn), these nitrofurans depend on Ddn and possibly another F-dependent reductase for activation...Two of the compounds, HC2233 and HC2234, were found to have potent, sterilizing activity against replicating and non-replicating Mtb in vitro, but a proposed mechanism of action could not be defined. In a pilot in vivo efficacy study, HC2210 was orally bioavailable and efficacious in reducing bacterial load by ~1 log in a chronic murine TB infection model.
- | Journal: A Rational Approach To Antitubercular Drug Design: Molecular Docking, Prediction of ADME Properties and Evaluation of Antitubercular Activity of Novel Isonicotinamide Scaffold. (Pubmed Central) - Sep 19, 2023
In a pilot in vivo efficacy study, HC2210 was orally bioavailable and efficacious in reducing bacterial load by ~1 log in a chronic murine TB infection model. This investigation helps in the development of better anti-tubercular therapy.
- | Journal: Discovery of novel reversible inhibitor of DprE1 based on benzomorpholine for the treatment of tuberculosis. (Pubmed Central) - Sep 12, 2023
This investigation helps in the development of better anti-tubercular therapy. We report that compound B18, a decaprenylphosphoryl-?-D-ribose 2
- | Journal: Design and synthesis of benzofuran- and naphthalene-fused thiazinones as antimycobacterial agents. (Pubmed Central) - Sep 7, 2023
In vitro testing showed micromolar activity for both compounds, and molecular docking simulations provided insights into their reduced inhibitory capacity toward the enzymatic target (DprE1). Calculated electrochemical potentials revealed a lower susceptibility to reduction as opposed to BTZ drug candidates, in line with the mechanistic requirement for covalent binding.
- | Journal: Design, synthesis, biological evaluation and molecular dynamics of some novel 3-phenylpyrazolo[1,5-a]pyrimidine-2,7(1H,4H)-dione based compounds as anti-tubercular agents. (Pubmed Central) - Sep 1, 2023
ADMET predictions for all the compounds revealed that these compounds have drug-like and lead-like properties. One of the final compounds was found to exhibit potent anti-TB activity against Mycobacterium bovis.Communicated by Ramaswamy H. Sarma.
- | Journal: Discovery of pyrimidine-tethered benzothiazole derivatives as novel anti-tubercular agents towards multi- and extensively drug resistant Mycobacterium tuberculosis. (Pubmed Central) - Aug 31, 2023
One of the final compounds was found to exhibit potent anti-TB activity against Mycobacterium bovis.Communicated by Ramaswamy H. Sarma. Compounds 5c and 15 having the highest anti-tubercular efficiency towards sensitive strain, displayed the best activity for the resistant strains by showing the MIC = 0.98 and 1.95
- | macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation
Journal: Side Chain-Modified Benzothiazinone Derivatives with Anti-Mycobacterial Activity. (Pubmed Central) - Jul 29, 2023
The benzothiazinone (BTZ) scaffold PBTZ169 kills Mycobacterium tuberculosis (Mtb) through the inhibition of the essential cell wall enzyme decaprenylphosphoryl-?-D-ribose 2'-oxidase (DprE1)...The representative compound 37 displays improved solubility and bioavailability compared to the lead compound. Additionally, compound 37 shows Mtb-killing ability in an acute infection mouse model.
- || Review, Journal: Recent advances in the synthesis of new benzothiazole based anti-tubercular compounds. (Pubmed Central) - Jul 24, 2023
Synthesis of benzothiazole derivatives was achieved through various synthetic pathways including diazo-coupling, Knoevenagel condensation, Biginelli reaction, molecular hybridization techniques, microwave irradiation, one-pot multicomponent reactions etc. Other than recent synthetic developments, mechanism of resistance of anti-TB drugs is also incorporated in this review. Structure activity relationships of the new benzothiazole derivatives along with the molecular docking studies of selected compounds have been discussed against the target DprE1 in search of a potent inhibitor with enhanced anti-tubercular activity.
- | Journal: Identification of a Chemical Inhibitor with a Novel Scaffold Targeting Decaprenylphosphoryl-?-D-Ribose Oxidase (DprE1). (Pubmed Central) - Jul 21, 2023
Structure activity relationships of the new benzothiazole derivatives along with the molecular docking studies of selected compounds have been discussed against the target DprE1 in search of a potent inhibitor with enhanced anti-tubercular activity. The structural analysis of the novel scaffold in Compound 4 can pave way for antituberculosis drug development and discovery.
- | Journal: 2,6-Disubstituted 7-(naphthalen-2-ylmethyl)-7H-purines as a new class of potent antitubercular agents inhibiting DprE1. (Pubmed Central) - Jul 19, 2023
Inhibition of DprE1 by 2,6-disubstituted 7-(naphthalen-2-ylmethyl)-7H-purines was proved using radiolabelling experiments in Mtb HRv in vitro. Finally, structure-binding relationships between selected purines and DprE1 using molecular modeling studies in tandem with molecular dynamic simulations revealed the key structural features for effective drug-target interaction.
- | macozinone (PBTZ169) / Innovative Medicines for Tuberculosis, Nearmedic, Bill & Melinda Gates Foundation
Journal: Quinolone analogues of benzothiazinone: Synthesis, antitubercular structure-activity relationship and ADME profiling. (Pubmed Central) - Jul 19, 2023
The most potent and developmentally advanced DprE1 inhibitor, PBTZ169, is still undergoing clinical development...Compound 25 further demonstrated sub-micromolar activity when evaluated against wild-type and fluoroquinolone-resistant Mtb strains. This compound maintained its sub-micromolar activity against a DprE1 P116S mutant strain but showed a significant reduction in activity when tested against the DprE1 C387S mutant.