anti-TB Agents Research Articles

Serial electrocardiogram recordings revealed a high prevalence of QT interval prolongation in patients with tuberculosis receiving fluoroquinolones

Fluoroquinolones, crucial components of treatment regimens for drug-resistant tuberculosis (TB), are associated with QT interval prolongation and risks of fatal cardiac arrhythmias. However, few studies have explored dynamic changes in the QT interval in patients receiving QT-prolonging agents. This prospective cohort study recruited hospitalized patients with TB who received fluoroquinolones. The study investigated the variability of the QT interval by using serial electrocardiograms (ECGs) recorded four times daily. This study analyzed the accuracy of intermittent and single-lead ECG monitoring in detecting QT interval prolongation. This study included 32 patients. The mean age was 68.6±13.2 years. The results revealed mild-to-moderate and severe QT interval prolongation in 13 (41%) and 5 (16%) patients, respectively. The incremental yields in sensitivity of one to four daily ECG recordings were 61.0%, 26.1%, 5.6%, and 7.3% in detecting mild-to-moderate QT interval prolongation, and 66.7%, 20.0%, 6.7%, and 6.7% in detecting severe QT interval prolongation. The sensitivity levels of lead II and V5 ECGs in detecting mild-to-moderate and severe QT interval prolongation exceeded 80%, and their specificity levels exceeded 95%. This study revealed a high prevalence of QT interval prolongation in older patients with TB who receive fluoroquinolones, particularly those with multiple cardiovascular risk factors. Sparsely intermittent ECG monitoring, the prevailing strategy in active drug safety monitoring programs, is inadequate owing to multifactorial and circadian QT interval variability. Additional studies performing serial ECG monitoring are warranted to enhance the understanding of dynamic QT interval changes in patients receiving QT-prolonging anti-TB agents.

Potential Repurposed Drug Candidates for Tuberculosis Treatment: Progress and Update of Drugs Identified in Over a Decade.

The devastating impact of Tuberculosis (TB) has been a menace to mankind for decades. The World Health Organization (WHO) End TB Strategy aims to reduce TB mortality up to 95% and 90% of overall TB cases worldwide, by 2035. This incessant urge will be achieved with a breakthrough in either a new TB vaccine or novel drugs with higher efficacy. However, the development of novel drugs is a laborious process involving a timeline of almost 20-30 years with huge expenditure; on the other hand, repurposing previously approved drugs is a viable technique for overcoming current bottlenecks in the identification of new anti-TB agents. The present comprehensive review discusses the progress of almost all the repurposed drugs that have been identified to the present day (∼100) and are in the development or clinical testing phase against TB. We have also emphasized the efficacy of repurposed drugs in combination with already available frontline anti-TB medications along with the scope of future investigations. This study would provide the researchers a detailed overview of nearly all identified anti-TB repurposed drugs and may assist them in selecting the lead compounds for further in vivo/clinical research.

Identification of anti-Mycobacterium tuberculosis agents targeting the interaction of bacterial division proteins FtsZ and SepFe.

Tuberculosis (TB) is one of the deadly diseases caused by Mycobacterium tuberculosis (Mtb), which presents a significant public health challenge. Treatment of TB relies on the combination of several anti-TB drugs to create shorter and safer regimens. Therefore, new anti-TB agents working by different mechanisms are urgently needed. FtsZ, a tubulin-like protein with GTPase activity, forms a dynamic Z-ring in cell division. Most of FtsZ inhibitors are designed to inhibit GTPase activity. In Mtb, the function of Z-ring is modulated by SepF, a FtsZ binding protein. The FtsZ/SepF interaction is essential for FtsZ bundling and localization at the site of division. Here, we established a yeast two-hybrid based screening system to identify inhibitors of FtsZ/SepF interaction in M. tuberculosis. Using this system, we found compound T0349 showing strong anti-Mtb activity but with low toxicity to other bacteria strains and mice. Moreover, we have demonstrated that T0349 binds specifically to SepF to block FtsZ/SepF interaction by GST pull-down, fluorescence polarization (FP), surface plasmon resonance (SPR) and CRISPRi knockdown assays. Furthermore, T0349 can inhibit bacterial cell division by inducing filamentation and abnormal septum. Our data demonstrated that FtsZ/SepF interaction is a promising anti-TB drug target for identifying agents with novel mechanisms.

High-throughput fluorescent screening of thioredoxin reductase inhibitors to inhibit Mycobacterium tuberculosis

Tuberculosis (TB) is a chronic infectious disease, which is caused by the pathogen Mycobacterium tuberculosis (Mtb) and reemerged as a global health risk with a significant proportion of multi-drug resistant and extensively drug resistant TB cases. It is very urgent to find some novel high-confidence drug targets in Mtb for discovering the effective anti-TB agents. Thioredoxin reductase (TrxR) has been identified to be a highly viable target for anti-TB drugs for its important role in protecting the pathogen from thiol-specific oxidizing stress, regulating intracellular dithiol/disulfide homeostasis and DNA replication and repair. In the present work, a near-infrared (NIR) fluorescent probe DDAT was developed for the detection of TrxR activity and used to high-throughput screen the TrxR inhibitors from natural products. Two screened TrxR inhibitors from Sappan Lignum and microbial metabolites that were further used to inhibit Mycobacterium tuberculosis. All the results indicate that DDAT is a practical fluorescent molecular tool for the discovery of potential anti-TB drugs.

Natural products and their analogues acting against Mycobacterium tuberculosis: A recent update.

Tuberculosis (TB) remains one of the deadliest infectious diseases caused by Mycobacterium tuberculosis (M.tb). It is responsible for significant causes of mortality and morbidity worldwide. M.tb possesses robust defense mechanisms against most antibiotic drugs and host responses due to their complex cell membranes with unique lipid molecules. Thus, the efficacy of existing front-line drugs is diminishing, and new and recurring cases of TB arising from multidrug-resistant M.tb are increasing. TB begs the scientific community to explore novel therapeutic avenues. A precise knowledge of the compounds with their mode of action could aid in developing new anti-TB agents that can kill latent and actively multiplying M.tb. This can help in the shortening of the anti-TB regimen and can improve the outcome of treatment strategies. Natural products have contributed several antibiotics for TB treatment. The sources of anti-TB drugs/inhibitors discussed in this work are target-based identification/cell-based and phenotypic screening from natural products. Some of the recently identified natural products derived leads have reached clinical stages of TB drug development, which include rifapentine, CPZEN-45, spectinamide-1599 and1810. We believe these anti-TB agents could emerge as superior therapeutic compounds to treat TB over known Food and Drug Administration drugs.

Structure-directed identification of pyridine-2-methylamine derivatives as MmpL3 inhibitors for use as antitubercular agents

Mycobacterial membrane protein Large 3 (MmpL3), an inner membrane protein, plays a crucial role in the transport of mycolic acids that are essential for the viability of M. tuberculosis and has been a promising therapeutic target for new anti-TB agents. Herein, we report the discovery of pyridine-2-methylamine antitubercular compounds using a structure-based drug design strategy. Compound 62 stands out as the most potent compound with high activity against M. tb strain H37Rv (MIC = 0.016 μg/mL) as well as the clinically isolated strains of MDR/XDR-TB (MIC = 0.0039–0.0625 μg/mL), low Vero cell toxicity (IC50 ≥ 16 μg/mL), and moderate liver microsomal stability (CLint = 28 μL/min/mg). Furthermore, the resistant mutant of S288T due to single nucleotide polymorphism in mmpL3 was resistant to pyridine-2-methylamine 62, demonstrating compound 62 is likely target to MmpL3.

Design, synthesis, characterization, and anti-tubercular activity of novel ethyl-3-benzoyl-6, 8-difluoroindolizine-1-carboxylate analogues: Molecular target identification and molecular docking studies

A series of novel Ethyl-3-benzoyl-6,8-difluoroindolizine-1-carboxylate analogues (4a-r) were synthesized by reacting 3,5-difluoropyridine, with phenacyl bromide to get quaternary pyridinium N-ylide in the presence of acetone and potassium iodide as a catalyst, further these pyridinium N-ylide intermediate reacts with various electron-deficient acetylenes, to get Ethyl-3-benzoyl-6,8-difluoroindolizine-1-carboxylate analogues (4a-r). All newly synthesized compounds were characterized by spectroscopic techniques such as 1H NMR, 13C NMR, IR, and HRMS. All the synthesized intermediates and final compounds were evaluated for their anti-tubercular activities against M. tuberculosis H37Rv (ATCC 27294). All the compounds exhibited anti-tuberculosis activity in the range of 6.25–50 µM against H37Rv. In silico evaluation of pharmacokinetic properties indicated overall drug-likeness for these compounds. The molecular target identification for these compounds was also carried out using a computational method approach. Docking studies were performed to investigate the binding affinities as well as the interaction of these compounds with target proteins. In this study, 4h, 4b, and 4o emerged as the promising anti-TB agents against M. tuberculosis H37Rv, with MIC99 values of 2.61 µg/mL, 4.67 µg/mL, and 5.02 µg/mL respectively.

Co-Delivery of D-LAK Antimicrobial Peptide and Capreomycin as Inhaled Powder Formulation to Combat Drug-Resistant Tuberculosis

IntroductionThe emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) posed a severe challenge to tuberculosis (TB) management. The treatment of MDR-TB involves second-line anti-TB agents, most of which are injectable and highly toxic. Previous metabolomics study of the Mtb membrane revealed that two antimicrobial peptides, D-LAK120-A and D-LAK120-HP13, can potentiate the efficacy of capreomycin against mycobacteria.AimsAs both capreomycin and peptides are not orally available, this study aimed to formulate combined formulations of capreomycin and D-LAK peptides as inhalable dry powder by spray drying.Methods and ResultsA total of 16 formulations were prepared with different levels of drug content and capreomycin to peptide ratios. A good production yield of over 60% (w/w) was achieved in most formulations. The co-spray dried particles exhibited spherical shape with a smooth surface and contained low residual moisture of below 2%. Both capreomycin and D-LAK peptides were enriched at the surface of the particles. The aerosol performance of the formulations was evaluated with Next Generation Impactor (NGI) coupled with Breezhaler®. While no significant difference was observed in terms of emitted fraction (EF) and fine particle fraction (FPF) among the different formulations, lowering the flow rate from 90 L/min to 60 L/min could reduce the impaction at the throat and improve the FPF to over 50%.ConclusionsOverall, this study showed the feasibility of producing co-spray dried formulation of capreomycin and antimicrobial peptides for pulmonary delivery. Future study on their antibacterial effect is warranted.

Engineering zinc oxide hybrid selenium nanoparticles for synergetic anti-tuberculosis treatment by combining Mycobacterium tuberculosis killings and host cell immunological inhibition.

As a deadly disease induced by Mycobacterium tuberculosis (Mtb), tuberculosis remains one of the top killers among infectious diseases. The low intracellular Mtb killing efficiency of current antibiotics introduced the long duration anti-TB therapy in clinic with strong side effects and increased drug-resistant mutants. Therefore, the exploration of novel anti-TB agents with potent anti-TB efficiency becomes one of the most urgent issues for TB therapies. Here, we firstly introduced a novel method for the preparation of zinc oxide-selenium nanoparticles (ZnO-Se NPs) by the hybridization of zinc oxide and selenium to combine the anti-TB activities of zinc oxide nanoparticles and selenium nanoparticles. We characterized the ZnO-Se NPs by dynamic laser light scattering and transmission electron microscopy, and then tested the inhibition effects of ZnO-Se NPs on extracellular Mtb by colony-forming units (CFU) counting, bacterial ATP analysis, bacterial membrane potential analysis and scanning electron microscopy imaging. We also analyzed the effects of ZnO-Se NPs on the ROS production, mitochondrial membrane potential, apoptosis, autophagy, polarization and PI3K/Akt/mTOR signaling pathway of Mtb infected THP-1 macrophages. At last, we also tested the effects of ZnO-Se NPs on intracellular Mtb in THP-1 cells by colony-forming units (CFU) counting. The obtained spherical core-shell ZnO-Se NPs with average diameters of 90 nm showed strong killing effects against extracellular Mtb, including BCG and the virulent H37Rv, by disrupting the ATP production, increasing the intracellular ROS level and destroying the membrane structures. More importantly, ZnO-Se NPs could also inhibit intracellular Mtb growth by promoting M1 polarization to increase the production of antiseptic nitric oxide and also promote apoptosis and autophagy of Mtb infected macrophages by increasing the intracellular ROS, disrupting mitochondria membrane potential and inhibiting PI3K/Akt/mTOR signaling pathway. These ZnO-Se NPs with synergetic anti-TB efficiency by combining the Mtb killing effects and host cell immunological inhibition effects were expected to serve as novel anti-TB agents for the development of more effective anti-TB strategy.

Regioselective Pd-Catalyzed Suzuki–Miyaura Borylation Reaction for the Dimerization Product of 6-Bromoimidazo[1,2-a]pyridine-2-carboxylate: Mechanistic Pathway, Cytotoxic and Tubercular Studies

AbstractIn the pharmaceutical industry, boronic acid and esters play an important role in API-based synthesis. The most efficient way of preparing various active agents is palladium-catalyzed Suzuki–Miyaura borylation reactions. Herein, we report the formation of dimerization product [6,6′-biimidazo[1,2-a]pyridine]-2,2′-dicarboxamide derivatives 7a–j from 6-bromoimidazo[1,2-a]pyridine-2-carboxylate by employing the same conditions. A regioselective borylation of ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate (3) was examined for the formation of ethyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-2-carboxylate (4a) but it was found to be directed towards the dimerization product 5. The nitrogen-rich system was incorporated into potential anti-cancer and anti-TB agents through acid amine coupling reactions between acid 6 and various amines (dialkyl/cyclic sec./tert.) to form the final adducts 7. Five derived scaffolds were identified as moderately active in TB activity against the H37Rv strain, while two compounds were found to be particularly potent in NCI-60 anti-cancer screening in nine cancer panels.

Investigation of 2-oxopyrrolidine 5-carboxylic acid amides derivatives as potential anti-tubercular agents based on the similarity screening results from molecular fingerprints and swiss similarity

Many open source in silico tools are available for drug discovery, this paper attempts to correlate the results obtained from two such tools with results obtained from in vitro screening. Discovery of novel Anti-TB agents became a necessity due to the ever increasing problem of drug resistance. As heterocyclic compounds are known to possess potent biological activity, here an attempt has been made to synthesize pyrazolidine derivatives from pyroglutamic acid. Further the synthesized derivatives are analyzed by IR, NMR and Mass spectral studies and screened for anti-tubercular and antimicrobial activity.

In-silico investigation and drug likeliness studies of benzimidazole congeners: The new face of innovation

BackgroundThe primary driving force behind the development of several small molecules for the treatment of tuberculosis is multi-drug resistance. A new fluorinated heterocyclic benzimidazole derivative gives extensive pharmacological activity against the FtsZ protein. FtsZ is a new validated target for tuberculosis drug design. It is a cell division filament protein present in Mycobacterium tuberculosis and other bacteria. MethodsLigand preparation- The ligand molecules were selected from the previously published paper and analyzed for reliability with the FtsZ protein. The 3D structure of the ligand was prepared using Chem-Draw Pro (version 12.0). Protein preparation- The PDB format FtsZ protein was downloaded from RCSB (https://www.rcsb.org/). The FtsZ protein of PDBID 2q1y was taken for the docking studies. The binding pocket was determined using the Castp server (http://sts.bioe.uic.edu/castp/index.html?201l). Thereafter, the in-silico docking was performed using PyRx 1.0 software. ResultThe docking result explains the importance of benzimidazole derivatives as potential FtsZ inhibitors. This study was focused on the in-silico development of new inhibitors and their chances to develop the candidate for oral delivery. The binding free energy, ADMET properties, and druglikeness characteristic of benzimidazole derivatives make them a perfect candidate for FtsZ inhibitors. Compound A-21 and A-20 had the best binding energy of −9.0 kcal/mol and −8.9 kcal/mol respectively. Molecular docking study revealed that Asn41, Thr42, Gly69, and Ala70 are required for conventional hydrogen bonding. The majority of the compounds (A-1, A-23 to A-32) are substrates for P-gp, which implies that their concentration inside the cell remain low due to P-efflux mechanism. ConclusionCompound A-20 formed five H-bond with target proteins (Gln30, Thr200, Gly226, Asp296, Val305). Almost all the molecules fulfil the criteria of drug likeliness. From this result, it can be concluded that benzimidazole derivatives can be developed as a new anti-Tb agent.

Discovery of potent triterpenoid and limonoid compounds targeting Mycobacterium tuberculosis enoyl acyl carrier protein reductase (InhA): An in silico investigation

Drug resistance remains one of the primary concerns in treating tuberculosis (TB), making it imperative to find new and effective drug candidates for improved TB treatment. Enoyl acyl carrier protein reductase (InhA), an enzyme involved in mycolic acid biosynthesis, is crucial for anti-TB drug activity such as isoniazid (INH). Triterpenoids and limonoids are widespread in the plant kingdom and have gained much attention in their development as anti-TB agents. This study aims to examine the potential of triterpenoid and limonoid compounds as InhA inhibitors based on binding energy, interaction mode, and binding stability using docking and molecular dynamics (MD) investigation. Chisopatens A (−10.93 kcal/mol), 3-epi-cabraleahydroxy lactone (−9.85 kcal/mol), and 3-oxo-olean-11(12)en-28-oic acid (−9.73 kcal/mol), as well as 6α-(acetoxy)-14β,15β-epoxyazadirone (−9.77 kcal/mol), an azadirone-type limonoid derivative, have the best affinity for Leu63, Gly96, and Lys165 amino acid residues from InhA compared to native ligand (NAD) analyzed by docking studies. Chisopatens A, 3-epi-cabraleahydroxy lactone, and 3-oxo-olean-11(12)en-28-oic also had the best affinity for InhA based on MM-PBSA analysis, with values of −140.676 kJ/mol, −108.888 kJ/mol, and −162.605 kJ/mol, respectively. During dynamics studies, these compounds also showed good stability, protein compactness, and high-intensity interaction with InhA. These results strongly support future in-vitro studies to evaluate the efficacy of the hit compounds for treating INH-resistant MTB strains.

Design, synthesis and evaluation of 1-(1,5-bis(4-substituted phenyl)-2-methyl-1H-pyrrol-3-yl)-N-methylmethanamines as SERT inhibitors with potential antidepressant action.

BM212 is a potent anti-TB agent with pharmacophoric features similar to the antidepressant drug sertraline. The shape-based virtual screening of the DrugBank database on BM212 resulted in the identification of several CNS drugs with appreciable Tanimoto scores. The docking simulations also ascertained the selectivity of BM212 towards the serotonin reuptake transporter protein (SERT) with a docking score of -6.51 kcal mol-1. Based on the SAR data available for sertraline and other antidepressant drugs, we designed, synthesized and screened twelve 1-(1,5-bis(4-substituted phenyl)-2-methyl-1H-pyrrol-3-yl)-N-methylmethanamines (SA-1 to SA-12) for in vitro SERT inhibition and in vivo antidepressant activity. The compounds were screened for in vitro 5HT reuptake inhibition using the platelet model. Among the screened compounds, (1-(1,5-bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-yl)-N-methylmethanamine) showed the same serotonin uptake inhibition (absorbance 0.22) as that of the standard drug sertraline (absorbance 0.22). BM212 had an effect on 5-HT uptake, albeit a weaker one compared to the standard (absorbance 0.671). Further, SA-5 was screened for in vivo antidepressant activity using the unpredictable chronic mild stress (UCMS) protocol to induce depression in mice. The effect of BM212 and SA-5 on the behaviour of the animals was assessed and compared against the standard drug sertraline. SA-5 at 20 mg per kg body weight was found to have a statistically significant impact on the behaviour of depressed animals.

Macrophage-targeted nanoparticles mediate synergistic photodynamic therapy and immunotherapy of tuberculosis.

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) that poses a serious global public health threat. Due to the high incidence of adverse reactions associated with conventional treatment regimens, there is an urgent need for better alternative therapies. CpG oligodeoxynucleotides (CpG ODNs) are synthetic oligodeoxyribonucleotide sequences. They can induce a Th1-type immune response by stimulating Toll-like receptors (TLRs) in mammalian immune cells, thus killing Mtb. However, due to the negative charge and easy degradation of CpG ODNs, it is necessary to deliver them into cells using nanomaterials. PCN-224 (hereinafter referred to as PCN), as a metal-organic framework based on zirconium ions and porphyrin ligands, not only has the advantage of high drug loading capacity, but also the porphyrin molecule in it is a type of photosensitizer, which allows these nanocomposites to play a role in photodynamic therapy (PDT) while delivering CpG ODNs. In addition, since Mtb mainly exists in macrophages, targeting anti-TB agents to macrophages is helpful to improve the anti-TB effect. Phosphatidylserine (PS) is a biological membrane phospholipid that is normally found on the inner side of cell membranes in, for example, plant and mammalian cells. When apoptosis occurs, PS can flip from the inner side of the cell membrane to the surface of the cell membrane, displaying a specific "eat-me" signal that can be recognized by specific receptors on macrophages. Therefore, we can use this macrophage-targeting property of PS to construct bio-inspired targeted drug delivery systems. In this study, we constructed PCN-CpG@PS nanocomposites. PCN-CpG@PS, combining PDT and immunotherapy, is designed to target macrophages at the site of a lesion and kill latent Mtb. We physically characterized the nanocomposites and validated their bactericidal ability in vitro and their ability to stimulate the immune system in vivo. The results demonstrated that the targeted nanocomposites have certain in vitro antituberculosis efficacy with good safety.

New tetrahydropyrimidine-1,2,3-triazole clubbed compounds: Antitubercular activity and Thymidine Monophosphate Kinase (TMPKmt) inhibition

Two series of new tetrahydropyrimidine (THPM)-1,2,3-triazole clubbed compounds were designed, synthesized and screened for their antitubercular (anti-TB) activity against M. tuberculosis H37Rv strain using microplate alamar blue assay (MABA). The most active compounds 5c, 5d, 5e and 5f were further examined for their cytotoxicity against the growth of RAW 264.7 mouse macrophage cells using MTT assay. The four compounds showed safety profiles better than or comparable to that of ethambutol (EMB). These compounds were evaluated for their inhibition activity against mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt). Compounds 5c and 5e were the most potent exhibiting comparable inhibition activity to that of the natural substrate deoxythymidine monophosphate (dTMP). An in silico study was performed including docking of the most active compounds 5c and 5e into the TMPKmt (PDB: ID 1G3U) binding pocket in addition to prediction of their physicochemical and pharmacokinetic properties to explore the overall activity of these anti-TB candidates. Compounds 5c and 5e are promising anti-TB agents and TMPKmt inhibitors with acceptable oral bioavailability, physicochemical and pharmacokinetic properties.

Ethionamide and Prothionamide Based Coumarinyl-Thiazole Derivatives: Synthesis, Antitubercular Activity, Toxicity Investigations and Molecular Docking Studies.

The goal of this research work was to prepare and evaluate the antitubercular (anti-TB) activity of ethionamide (ETH) and prothionamide (PTH) based coumarinyl-thiazole derivatives. ETH and PTH were reacted with coumarin intermediates (3a-3e) to provide the target compounds (4a-4e and 4f-4j, respectively). Spectral studies confirmed the assigned structures of 4a-4j. The Microplate Alamar Blue Assay was utilized to evaluate the anti-TB activity of compounds 4a-4j against Mycobacterium tuberculosis H37Rv strain in comparison to ETH, PTH, isoniazid (INH), and pyrazinamide (PYZ) as standard drugs. The cytotoxicity studies were carried out versus HepG2 and Vero cell lines. In addition. molecular docking studies of 4a-4j concerning the DprE1 enzyme and the in-silico evaluation of physicochemical and pharmacokinetic parameters were performed. Compounds 4a, 4b, 4f, and 4g displayed equal minimum inhibitory concentration (MIC) values in comparison to INH (3.125 μg/ml) and PYZ (3.125 μg/ml), whereas 4c-4e and 4h-4j displayed better MIC values (1.562 μg/mL) than INH and PYZ. All compounds presented better anti-TB potential than ETH (6.25 μg/mL) and PTH (6.25 μg/mL). The studies of toxicity revealed that 4a-4j were safe up to 300 μg/mL concentration versus Vero and HepG2 cell lines. The molecular docking studies suggested that 4a-4j could possess anti-TB activity through the inhibition of the DprE1 enzyme. The in silico studies showed that 4a-4j followed Lipinski's rule (drug-likeliness) and exhibited better gastrointestinal absorption than BTZ043 and macozinone. In conclusion, the ETH and PTH-based coumarinyl-thiazole template can help developing selective DprE1 enzyme inhibitors as potent anti-TB agents.

Evidence for Implementation: Management of TB in HIV and Pregnancy.

Pregnant people living with HIV (PLWH) are at especially high risk for progression from latent tuberculosis infection (LTBI) to active tuberculosis (TB) disease. Among pregnant PLWH, concurrent TB increases the risk of complications such as preeclampsia, intrauterine fetal-growth restriction, low birth weight, preterm-delivery, perinatal transmission of HIV, and admission to the neonatal intensive care unit. The grave impact of superimposed TB disease on maternal morbidity and mortality among PLWH necessitates clear guidelines for concomitant therapy and an understanding of the pharmacokinetics (PK) and potential drug-drug interactions (DDIs) between antitubercular (anti-TB) agents and antiretroviral therapy (ART) in pregnancy. This review discusses the currently available evidence on the use of anti-TB agents in pregnant PLWH on ART. Pharmacokinetic and safety studies of anti-TB agents during pregnancy and postpartum are limited, and available data on second-line and newer anti-TB agents used in pregnancy suggest that several research gaps exist. DDIs between ART and anti-TB agents can decrease plasma concentration of ART, with the potential for perinatal transmission of HIV. Current recommendations for the treatment of LTBI, drug-susceptible TB, and multidrug-resistant TB (MDR-TB) are derived from observational studies and case reports in pregnant PLWH. While the use of isoniazid, rifamycins, and ethambutol in pregnancy and their DDIs with various ARTs are well-characterized, there is limited data on the use of pyrazinamide and several new and second-line antitubercular drugs in pregnant PLWH. Further research into treatment outcomes, PK, and safety data for anti-TB agent use during pregnancy and postpartum is urgently needed.

Isoxazole carboxylic acid methyl ester-based urea and thiourea derivatives as promising antitubercular agents.

In our continued efforts to find potential chemotherapeutics active against drug-resistant (DR) Mycobacterium tuberculosis (Mtb), causative agent of Tuberculosis (TB) and to curb the current burdensome treatment regimen, herein we describe the synthesis and biological evaluation of urea and thiourea variants of 5-phenyl-3-isoxazolecarboxylic acid methyl esters as promising anti-TB agent. Majority of the tested compounds displayed potent in vitro activity not only against drug-susceptible (DS) Mtb H37Rv but also against drug-resistant (DR) Mtb. Cell viability test against Vero cells deemed these compounds devoid of significant toxicity. 3,4-Dichlorophenyl derivative (MIC 0.25 µg/mL) and 4-chlorophenyl congener (MIC 1 µg/mL) among urea and thiourea libraries respectively exhibited optimum potency. Lead optimization resulted in the identification of 1,4-linked analogue of 3,4-dichlorophenyl urea derivative demonstrating improved selectivity. Further, in silico study complemented with previously proposed prodrug like attributes of isoxazole esters. Taken together, this molecular hybridization approach presents a new chemotype having potential to be translated into an alternate anti-Mtb agent. Graphical abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s11030-022-10543-0.

A Hydrazine-Hydrazone Adamantine Compound Shows Antimycobacterial Activity and Is a Probable Inhibitor of MmpL3.

Tuberculosis remains an important cause of morbidity and mortality throughout the world. Notably, an important number of multi drug resistant cases is an increasing concern. This problem points to an urgent need for novel compounds with antimycobacterial properties and to improve existing therapies. Whole-cell-based screening for compounds with activity against Mycobacterium tuberculosis complex strains in the presence of linezolid was performed in this study. A set of 15 bioactive compounds with antimycobacterial activity in vitro were identified with a minimal inhibitory concentration of less than 2 µg/mL. Among them, compound 1 is a small molecule with a chemical structure consisting of an adamantane moiety and a hydrazide–hydrazone moiety. Whole genome sequencing of spontaneous mutants resistant to the compounds suggested compound 1 to be a new inhibitor of MmpL3. This compound binds to the same pocket as other already published MmpL3 inhibitors, without disturbing the proton motive force of M. bovis BCG and M. smegmatis. Compound 1 showed a strong activity against a panel ofclinical strains of M. tuberculosis in vitro. This compound showed no toxicity against mammalian cells and protected Galleria mellonella larvae against M. bovis BCG infection. These results suggest that compound 1 is a promising anti-TB agent with the potential to improve TB treatment in combination with standard TB therapies.