Antitubercular Drugs Research Articles

Coexisting parathyroid adenoma, thyroid carcinoma, and tuberculosis of thyroid: a case report

BackgroundCoexisting parathyroid adenoma, thyroid carcinoma, and tuberculosis of thyroid is a very rare phenomenon. Primary thyroid tuberculosis is itself very rare despite high global prevalence of tuberculosis in developing countries. Majority of thyroid tuberculosis identified in postoperative histopathology or cytopathology. The coexistence of thyroid cancer with tuberculosis or parathyroid adenoma has been reported in the literature but not a single case of the three pathologies coexisting together has been found in the literature published. We are presenting a rare case of a constellation of synchronous parathyroid adenoma, thyroid carcinoma, and thyroid tuberculosis. This case report will provoke researchers to work on understanding the association of hypercalcemia or chronic inflammation leading to development of malignancy or parathyroid adenoma in the presence of hypothyroidism will give future perspective in managing such patients.Case presentationA Islam lady aged 45 years old, diagnosed with hypothyroidism, was evaluated for pregnancy loss and rapid weight gain from 13 years back and started on tablets of levothyroxine 25 µg once daily. She was doing well until the past 2 years; there after she noticed insidious onset of a swelling over anterior aspect of right side of the neck and bone pain in back and lower limbs. Patient underwent routine investigations and was found to have raised serum calcium (11.4 mg/dl) and parathyroid hormone (253 pg/ml). Anti-thyroid peroxidase (TPO) and anti-thyroglobulin (Tg) level were normal. Ultrasounds showed multiple nodules in both lobe of thyroid and left inferior parathyroid adenoma. The patient underwent total thyroidectomy with left inferior parathyroidectomy, and final histopathology showed features of subacute granulomatous thyroiditis along with hurthle cell change in right lobe of thyroid. The left lobe additionally showed necrotizing epitheloid cell granulomas, which on Zeihl–Neelson staining revealed presence of acid-fast bacilli. Sections from the isthmus show a focus of papillary thyroid microcarcinoma. The left inferior parathyroid gland sent as a frozen sample was found to be parathyroid adenoma. On 6-month follow-up, the patient was feeling much relief in bone pain and tolerating antitubercular drugs uneventfully.ConclusionCoexistence of parathyroid adenoma, nonmedullary thyroid carcinoma, and thyroid tuberculosis is extremely rare. Surgery is curative for hyper parathyroidism and thyroid carcinoma. Thyroid tuberculosis responds well to current antitubercular drugs. Its etiology needs to be explored more; the probable hypothesis is chronic inflammation due to latent tuberculosis might leads to development of thyroid carcinoma and parathyroid adenoma. Further studies need to be done for better understanding of underlying mechanism and better management options for such patients. To the best of our knowledge, similar cases have not been reported.

Structural Studies on Mycobacterial NudC Reveal a Class of Zinc Independent NADH Pyrophosphatase

Non-tuberculous mycobacteria (NTM) have emerged as an increasing threat to public health, due to the extreme antibiotic resistance. NADH pyrophosphatase (NudC) was proposed involving in mycobacterial resistance to the first line anti-tubercular drug isoniazid (INH) or its analog ethionamide (ETH), by hydrolyzing their NAD modified active forms (NAD-INH and NAD-ETH). In this study, we performed enzymatic and structural studies on NudC from M. abscessus (NudCMab), which is highly resistant to isoniazid and emerging as the most worrisome NTM. We determined the crystal structures of NudCMab in apo form, substrate NAD-bound form and product AMP-bound form. We observed the mode for the Nudix motif of NudCMab capturing the pyrophosphate group of NAD mediated by three divalent cation ions, which provides details for understanding the mechanism on NudC hydrolyzing NAD(H) or NAD-capped substrate. Interestingly, our structures revealed a novel subclass NudC from mycobacteria characterized by a unique arginine residue on the conserved QPWPFPxS motif, as well as a unique tower domain that replaces a well-defined zinc-binding motif in E.coli NudC and catalytic domain of mammalian Nudt12. Thus, our structural studies on NudCMab not only present a class of zinc independent NADH pyrophosphatase in mycobacteria, but also may facilitate the design of NudC inhibitors for the treatment of mycobacteria infections in combination with INH or ETH.

A case report of intrapulmonary mature teratoma with aspergilloma

Introduction: Teratomas are benign germ cell tumors composed of components from the ectoderm, mesoderm, and endoderm. While germ cell tumors account for 10-20% of anterior mediastinal masses, intrapulmonary teratomas (IPTs) are extremely rare. They typically occur in the third decade of life and may present as metastasis from gonadal tumors. This study reports a rare case of a mature IPT in the right middle lobe of the lung, initially misdiagnosed as pulmonary tuberculosis and aspergilloma. Case Presentation: A 17-year-old female presented with a 4-year history of cough with sputum and two episodes of hemoptysis. Despite negative tuberculosis tests, she was treated with anti-tubercular drugs and multiple antibiotics. Imaging revealed a 5.5-cm cavitary mass in the right middle lobe containing an aspergilloma. Surgical resection was performed, and the pathology confirmed a mature teratoma with aspergilloma colonization. The patient recovered well postoperatively and showed no signs of recurrence. Discussion: Teratomas are germ cell tumors rarely found in the lungs, with fewer than 100 cases reported globally. Diagnosis is challenging due to overlapping symptoms with other conditions such as tuberculosis. In this case, the presence of an aspergilloma further complicated the diagnosis. Complete surgical resection led to the patient's recovery. Conclusion: Mature IPTs with aspergilloma are extremely rare, and should be considered in the differential diagnosis of cavitary lung lesions. Early diagnosis and surgical resection are crucial for successful treatment.

DBUH][HSO4]-catalyzed Solvent-free Synthesis of 1,5-benzodiazepine Derivatives: Bioevaluation and In silico Molecular Docking Study

: Here, we report the solvent-free one-pot multicomponent synthesis of 4- substituted-1,5-benzodiazepine derivatives from O-phenylenediamine, aromatic aldehydes, and dimedone using [DBUH][HSO4] as a catalyst in excellent yields. This process was carried out in search of a reusable, easily accessible, affordable, and efficient catalyst. 1,5- Benzodiazepines demonstrate a new family of good inhibitors with potent antimycobacterial properties. The most promising compounds in the present series are 4c, 4i, and 4l which showed excellent activity and inhibited the growth of both MTB H37Ra and M. bovis BCG strains with lower MICs. The most active compounds were further studied for their cytotoxicity against cell lines MCF-7, A549, HCT116, and THP-1 by MTT assays and the compounds were found to be non-toxic. The fact that none of these compounds work against either Gram-positive or Gram-negative bacteria suggests that they are only effective against MTB. The in silico docking of the molecules against mycobacterial enoyl reductase, InhA enzyme could provide well-clustered solutions and have given valuable insights into the thermodynamic elements governing the binding affinities. The findings of this investigation unmistakably point to the discovery of extremely specific and selective MTB inhibitors, which can now be investigated further in search of possible anti-tubercular drugs.

Thiol Stress Fuels Pyrazinamide Action Against Mycobacterium tuberculosis.

Pyrazinamide is the only antitubercular drug of its kind, capable of targeting persistent Mycobacterium tuberculosis through disruption of the coenzyme A biosynthetic pathway. A peculiar feature of this drug is that its activity is conditional, requiring low pH for its action. Despite decades of investigation, the precise basis for this conditional susceptibility has remained elusive which has been a barrier to discovery of more effective next-generation analogs. Using approaches in chemical biology, functional genomics and bacterial physiology we demonstrate that activation of thiol stress is the basis for pyrazinamide potentiation. These findings resolve a long-standing question regarding the mechanistic basis for conditional PZA susceptibility of M. tuberculosis and reveal novel avenues for antimicrobial drug discovery efforts.

A Case of Atypical Drug-Induced Hypersensitivity Syndrome While Taking Anti-Tubercular Drugs

A Case of Atypical Drug-Induced Hypersensitivity Syndrome While Taking Anti-Tubercular Drugs

Pharmaceutical salt of isoniazid−orotic acid with optimized solubility, dissolution rate, and tabletability

Isoniazid (INH) is a first-line antitubercular drug characterized by its high solubility and rapid absorption following oral administration, which poses challenges in maintaining sustained therapeutic concentrations. To address this issue, we have developed a novel pharmaceutical salt of INH with orotic acid (OA). Single-crystal X-ray diffraction (XRD) analysis revealed that intermolecular proton transfer occurs between the carboxyl group of OA and the pyridine nitrogen site of INH, resulting in a salt comprising INHH+ cations and OA− anions. Solubility and dissolution studies indicated that INH−OA exhibits significantly reduced solubility and decelerated intrinsic dissolution rate (IDR). Specifically, solubility reductions were observed to be 74.24% in pH 1.2 HCl solution and 90.29% in pH 6.8 phosphate buffer solution. The IDR of the salt was found to be 2.62% and 0.96% of that of pure INH in pH 1.2 and pH 6.8 aqueous media, respectively. Additionally, INH−OA demonstrated improved tabletability. These findings suggest that the formation of this salt significantly enhances the pharmaceutical properties of INH.

An observational study on the spectrum of Cutaneous Adverse Reactions to Antitubercular drugs and their management

IntroductionTuberculosis (TB) remains a significant global health issue, ranking as the 13th leading cause of death worldwide. Management of tuberculosis requires administration of multiple drugs for varied duration which increases the risk of developing adverse reactions. Among various adverse reactions are cutaneous adverse reactions (CARs) which can be immune mediated or non immune mediated. Aim1. To study the clinical, epidemiological, and morphological characteristics of cutaneous adverse reactions resulting from antitubercular treatment. 2. To study the outcomes of cutaneous adverse reactions to antitubercular therapy using the Modified Hartwig and Seigel severity assessment scale and rechallenge protocol, and assess the effectiveness of management strategies. Methodology: A longitudinal observational study was conducted over a period of 1 year at department of Pulmonology and Dermatology at tertiary care institute to assess CARs in patients on antitubercular treatment. Rechallenge was done in eligible patients. ResultsAmong 3164 TB patients on anti-tubercular treatment (ATT), 56 developed CARs, yielding an incidence rate of 1.77% per year. The study found female preponderance, with the most affected age groups being 21-30 and 41-50 years. Most CARs occurred within the first 30 days of ATT initiation, predominantly manifesting as maculopapular rash. Factors such as multiple medication use, diabetes, elderly age, and positive HIV status were associated with CARs. Ethambutol was identified as the most frequently implicated drug in the occurrence of cutaneous adverse reactions (CARs) upon rechallenge. ConclusionEffective management of CARs involves appropriate treatment, careful monitoring, and rechallenge protocols to identify culprit drugs while minimizing the risk of severe reactions.Upon complete resolution of initial adverse reaction, one must do rechallenge meticulously to pinpoint culprit drug and ensuring effective tuberculosis treatment.

A virulence-associated small RNA MTS1338 activates an ABC transporter CydC for rifampicin efflux in Mycobacterium tuberculosis.

The efficacy of the tuberculosis treatment is restricted by innate drug resistance of Mycobacterial tuberculosis and its ability to acquire resistance to all anti-tuberculosis drugs in clinical use. A profound understanding of bacterial ploys that decrease the effectiveness of drugs would identify new mechanisms for drug resistance, which would subsequently lead to the development of more potent TB therapies. In the current study, we identified a virulence-associated small RNA (sRNA) MTS1338-driven drug efflux mechanism in M. tuberculosis. The treatment of a frontline antitubercular drug rifampicin upregulated MTS1338 by >4-fold. Higher intrabacterial abundance of MTS1338 increased the growth rate of cells in rifampicin-treated conditions. This fact was attributed by the upregulation of an efflux protein CydC by MTS1338. Gel-shift assay identified a stable interaction of MTS1338 with the coding region of cydC mRNA thereby potentially stabilizing it at the posttranscriptional level. The drug efflux measurement assays revealed that cells with higher MTS1338 abundance accumulate less drug in the cells. This study identified a new regulatory mechanism of drug efflux controlled by an infection-induced sRNA in M. tuberculosis.

Discovery of anti-infective compounds against Mycobacterium marinum after biotransformation of simple natural stilbenes by a fungal secretome.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, remains a serious threat to human health worldwide and the quest for new anti-tubercular drugs is an enduring and demanding journey. Natural products (NPs) have played a significant role in advancing drug therapy of infectious diseases. This study evaluated the suitability of a high-throughput infection system composed of the host amoeba Dictyostelium discoideum (Dd) and Mycobacterium marinum (Mm), a close relative of Mtb, to identify anti-infective compounds. Growth of Dd and intracellular Mm were quantified by using luminescence and fluorescence readouts in phenotypic assays. The system was first benchmarked with a set of therapeutic anti-Mtb antibiotics and then used to screen a library of biotransformed stilbenes. The study confirmed both efficacy of established antibiotics such as rifampicin and bedaquiline, with activities below defined anti-mycobacterium susceptibility breakpoints, and the lack of activity of pyrazinamide against Mm. The screening revealed the promising anti-infective activities of trans-δ-viniferins and in particular of two compounds 17 and 19 with an IC50 of 18.1 μM, 9 μM, respectively. Both compounds had no activity on Mm in broth. Subsequent exploration via halogenation and structure-activity relationship studies led to the identification of derivatives with improved selectivity and potency. The modes of action of the anti-infective compounds may involve inhibition of mycobacterial virulence factors or boosting of host defense. The study highlights the potential of biotransformation and NP-inspired derivatization approaches for drug discovery and underscores the utility of the Dd-Mm infection system in identifying novel anti-infective compounds.

Pharmacokinetics-pharmacodynamics of first-line antitubercular drugs: a comparative study in tuberculosis patients with and without concomitant diabetes mellitus.

To observe the variability in the plasma concentrations and pharmacokinetic-pharmacodynamic (PK-PD) profiles of first-line antitubercular drugs in pulmonary tuberculosis (TB) patients with and without diabetes mellitus (DM). Newly diagnosed pulmonary TB patients aged 18-60years with or without DM were included in the study. Group I (n = 20) included patients with TB, whereas group II (n = 20) included patients withboth TB and DM. After 2 weeks of therapy, plasma concentrations and other PK-PD parameters were determined. Improvements in clinical features, X-ray findings, sputum conversion, and adverse drug reactions (ADRs) were assessed after 2 months of therapy. Isoniazid displayed non-significantly higher plasma concentrations in diabetic patients, along with a significantly (P < 0.05) longer elimination half-life (t1/2). Rifampicin plasma concentrations at 4, 8, and 12 h were significantly (P < 0.05) lower, and it displayed significantly (P < 0.05) lower area underthe curve (AUC0-12 and AUC0-∞), shorter t1/2, higher clearance (Cl), and a lower AUC0-∞/MIC ratio in diabetic patients. Pyrazinamide and ethambutol showed non-significantly higher plasma concentrations, AUC0-12, AUC0-∞, and t1/2 in diabetic patients. The improvements in clinical features, X-ray findings, sputum conversion, and ADRs were comparable in both groups. The presence of DM in TB patients affects the PK-PD parameters of isoniazid, rifampicin, pyrazinamide, and ethambutol variably in the Indian population. Studies with a larger number of patients are required to further elucidate the role of DM on the PK-PD profile of first-line antitubercular drugs and treatment outcomes in TB patients with concomitant DM. CTRI/2021/08/035578 dated 11/08/2021.

Ethambutol induced optic neuropathy: A remerging ocular emergency needing strict vigilance and screening

: To investigate the clinical manifestations and incidence of ethambutol induced optic neuropathy (EON) and identify its risk factors.: A cross sectional, hospital based observational study was conducted in 100 patients, who were on anti-tubercular drugs (ATT) and complained of diminution of vision. The following data was collected in every patient regarding age, gender, co-morbid conditions, clinical manifestation of (tuberculosis)TB, duration and dose of ethambutol. Complete ophthalmic examination was conducted in every patient including best corrected visual acuity (BCVA), color vision, relative afferent pupillary defect (RAPD), fundus examination, visual field analysis and OCT RNFL &amp; GCL. Statistical analysis of the data was done and represented suitably using appropriate statistical tests that included Chi Square test for checking associations and T test for comparing quantitative data with the help of SPSS ver. 26.0 software. All p-values reported were two sided and a value less than 0.05 was considered significant. :Out of 100 patients, only 18 patients were diagnosed with EON and calculated incidence was 1.8%. The most common presenting feature of EON was bilateral diminution of vision (89%) followed by abnormal color vision (11%). On examination, RAPD was seen in 40% cases because of asymmetrical optic nerve involvement and disc abnormality was present in 66% cases. The duration and dose of ethambutol medication, advanced age (&amp;#62;65 years), hypertension, chronic smoking and presence of renal dysfunction were shown to be positively correlated with EON development.:At present, there is no effective treatment for EON except supplementation of zinc, copper, methylcobalamine and pyridoxine. Therefore, early detection and discontinuation of ethambutol is only way to prevent permanent loss of vision, as in early stage it is reversible.

Halogenated chalcones against Mycobacterium tuberculosis targeting InhA: Rational design, in silico and in vitro evaluation

A library of 25-series compounds was designed against Mycobacterium Tuberculosis (M.tb) to identify novel antitubercular drugs. In silico inhibition of InhA, an essential component of FAS-II, was successfully achieved. The drug ability, lead-likeness, and toxicity of the compounds were assessed using Swiss ADME, pkCSM, and Osiris Property Explorer, which revealed the potential for drug development of chalcone compounds. Through in silico research, it was confirmed that toxic-free compounds could bind to InhA. It was found that all of the compounds bind to InhA with binding affinities ranging from −7.78 to −10.29 kcal/mol−1 which is higher than the reference standard Isoniazid and Pyrazinamide. The top five compounds were synthesized from 15 toxic-free compounds. The structural characteristics of the compounds were determined using IR, NMR, and mass spectrometry techniques. These findings indicate that these substances are competitive, reversible, and specific InhA inhibitors of InhA. using the Alamar Blue assay method (H37RV, ATCC No. 27294), the in vitro anti-mycobacterial activity of each of the synthesized compounds against M.tb was evaluated. The two most powerful compounds were (2E)-3-[4-(benzyloxy)-3,5-dimethylphenyl] and (2E)-1-(3,5-dibromophenyl)-3-(3-phenoxyphenyl) prop-2-en-1-one. In the MABA Assay, the MIC for 1-(3,5-dibromophenyl) prop-2-en-1-one was 6.25 μg/ml.

Computational Exploration of Isatin Derivatives for InhA Inhibition in Tuberculosis: Molecular Docking, MD Simulations and ADMET Insights.

Anti-tubercular drug discovery is a critical research area aimed at addressing the global health burden imposed by Mycobacterium tuberculosis. Nowadays, computational techniques have increased the likelihood of drug development compared to traditional, labor-intensive, and time-consuming drug design approaches. The pivotal goal of drug design is to identify compounds capable of selectively targeting protein, thereby disrupting its enzymatic activity. InhA, or NADH-dependent enoyl-acyl carrier protein reductase, stands at the forefront of targeted approaches in the battle against TB. Isatin derivatives have garnered interest for their diverse pharmacological activities. To identify novel isatin derivatives that could serve as potential chemical templates for anti-TB drug discovery by targeting InhA. The present work utilized various computational approaches, including molecular docking, binding free energy calculations, and conformational alignment studies to investigate the binding mode and interactions of carefully selected dataset of 88 isatin derivatives within InhA active site. Study also employed MD simulations of the most promising molecule to check the stability of the protein-ligand complex and in-silico ADMET profiling of the top compounds to predict their pharmacokinetic and toxicity properties. Results provided insights into the structural features contributing to InhA inhibition, assessing overall drug-like characteristics of isatin derivatives and identified compound 48 (BA= -10.4 kcal mol-1 ) with potential for further optimization. MD simulation analysis revealed that compound 48 binds firmly within the InhA protein, exhibiting minimal conformational fluctuations and enhanced stability. Considering the aforementioned, isatin derivatives represents a novel framework for creating targeted InhA inhibitors during anti-TB therapy. However, experimental validations and in-depth analyses are crucial to confirm efficacy and safety of these derivatives as potential InhA inhibitors for TB treatment.

GENOMIC CHARACTERIZATION AND DRUG RESISTANCE PROFILES OF MYCOBACTERIUM TUBERCULOSIS LINEAGE 2 IN KAZAKHSTAN: PRELIMINARY RESULTS

Tuberculosis remains a highly contagious infection, with an estimated annual transmission of about 10 million people globally, as reported in the latest Global Tuberculosis Report by the World Health Organization (WHO). The primary objective of this research is to determine the geographical distribution and drug resistance profiles of Mycobacterium tuberculosis lineage 2, which is predominant in Kazakhstan. A total of over 200 clinical isolates of M. tuberculosis complex (MTBC) were collected from regional phthisiopulmonology centers across all regions of Kazakhstan between 2012 and 2024. Clinical isolates were genotyped using a PCR assay targeting the dnaA-dnaN:IS6110 region, specific for the modern Beijing genotype. Subsequently, selected samples were sequenced using the Illumina MiSeq platform. The TB-Profiler prediction tool was utilized to identify resistance against anti-tubercular drugs and to genotype the lineages. A total of 102 clinical isolates belonging to the L2 modern Beijing genotype were selected for whole-genome sequencing (WGS). The L2.2.1 genetic cluster was identified as the only sublineage present, according to Coll et al.'s classification. More than half of the specimens were found to be multidrug-resistant (n=60, 59%). Among the analyzed samples, monoresistance to isoniazid (IHN) was detected in 17 (16%) cases, while 14 (14%) cases were drug-susceptible TB. Additionally, 7 (7%) cases were identified as Pre-XDR (resistant to rifampicin, isoniazid, and either fluoroquinolones or second-line injectable drugs), 3 (3%) cases were monoresistant to streptomycin, and 1 (1%) case exhibited resistance to rifampicin only. Regional distribution of samples is as follows: Aktau and Kostanay are 14% (n=13/102), Kyzylorda (n=12/102), Taldykourgan (n=11/102), Pavlodar, Karaganda, and Atyrau are at 6% (6/102); Semey is 10% (n=9/102), Almaty and Taraz at 4%, and Shymkent city is 1% (n=1/102). This ongoing research is focused on resistance patterns, genotypes, and transmission dynamics among different regions of Kazakhstan using next-generation sequencing, followed by bioinformatics analysis and interpretation of the data.

Chemical genetic interactions elucidate pathways controlling tuberculosis antibiotic efficacy during infection.

The inevitable rise of multi-drug-resistant tuberculosis underscores the urgent need for new TB drugs and novel drug targets while prioritizing synergistic drug combinations. Chemical-genetic interaction (CGI) studies have delineated bacterial pathways influencing antibiotic efficacy and uncovered druggable pathways that synergize with TB drugs. However, most studies are conducted in vitro , limiting our understanding of how the host environment influences drug-mutant interactions. Using an inducible mutant library targeting essential Mtb genes to characterize CGIs during infection, this study reveals that CGIs are both drug-specific and drug-agnostic and differ significantly from those observed in vitro . Synergistic CGIs comprised distinct metabolic pathways mediating antibiotic efficacy, revealing novel drug mechanisms of action, and defining potential drug targets that would synergize with frontline antitubercular drugs.

Design, synthesis and antimycobacterial activity of novel benzothiazinones with improved water solubility

Nitrobenzothiazinones (BTZs) represent a novel type of antitubercular agents targeting DprE1. Two clinical candidates BTZ043 and PBTZ169, as well as many other BTZs showed potent anti-TB activity, but they are all highly lipophilic and their poor aqueous solubility is still a serious issue need to be addressed. 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: <0.029–0.095 μM), low toxicity and acceptable oral PK profiles, as well as significantly improved water solubility (1200 and > 2000 μg/mL, respectively), suggesting they may serve as promising hydrophilic BTZs for further antitubercular drug discovery.

Design, synthesis and docking studies of new molecular hybrids bearing benzimidazole and thiazolidine-2,4-dione as potential antitubercular agents

Finding novel therapeutic medications to combat tuberculosis (TB) is crucial, as evidenced by the disease's growth as a worldwide health concern in recent decades and the rise of drug-resistant forms of Mycobacterium tuberculosis (Mtb). In this article, we describe the synthesis and design of a novel class of thiazolidine-2,4-dione derivatives (5a-i) based on 1H-benzo [d]imidazoles as antitubercular drugs. Spectroscopic techniques and elemental analysis were used to characterize each of the newly synthesized molecules. The antitubercular activity of all the newly synthesized title compounds was assessed against drug-sensitive Mtb H37Rv, multidrug-resistant (MDR-TB), and extensively drug-resistant (XDR-TB) tuberculosis. Compounds 5e and 5 h had the most antitubercular activity among all the newly synthesized hybrids against drug-sensitive, MDR-TB, and XDR-TB strains, with MIC values ranging from 0.21 to 47.84 μM. When it comes to drug-sensitive, drug-resistant, and XDR Mtb strains, compound 5 h with a trifluoromethyl group is 1.71, 10.86, and 3.50 times more potent, whereas compound 5e with a nitro group is 1.12, 8.50, and 2.61 times more active. Remarkably, the compounds' in vitro cytotoxicity test demonstrated good selectivity indices, highlighting their safety on the normal lung fibroblast (WI-38) cell line experiment. To further understand the interactions between potent hybrids and the target enzyme, molecular docking investigations were conducted against the decaprenyl-phosphoryl-ribose 2′-epimerase (DprE1) enzyme. The target protein exhibited preferentially positive interactions with the potent compounds 5e, 5f, 5 h, and 5i. Relationships between structure-activity as well as drug-likeness were used to connect the freshly synthesized compounds' physical and biological properties. When considered collectively, these results suggest that compounds 5e and 5 h might be promising candidates for the development of drug-sensitive and drug-resistant TB therapies in the future.

Repurposing Drugs as Host-Directed Therapy in Tuberculosis

Abstract: Tuberculosis is a chronic infective respiratory disease that has been known to mankind for centuries and is still responsible for higher rates of morbidity and mortality globally. Repurposing drugs as host-directed therapies as an add-on drug to tuberculosis is a promising scope to study as it may have a significant impact in reducing the treatment duration and complications of tuberculosis. Host-directed therapy is a strategy to target the host and its immune mediators responsible for pro and anti-inflammatory pathways, thus modifying them with drugs to achieve increased bacterial clearance and reduced long-term inflammatory-mediated complications of tuberculosis. Various drugs approved for other indications have been studied in preclinical animal and in vitro studies, as well as clinical trials in tuberculosis. These drugs mainly aim to improve mycobacterial clearance and minimize post-TB consequences by suppressing inflammatory mediators. Drugs such as metformin, imatinib, vitamin D, and (Vascular Endothelial Growth Factors) VEGF drugs are studied for their ability to modulate the anti-inflammatory effects, and drugs, such as doxycycline, corticosteroids, and N-acetylcysteine are being studied for their role as proinflammatory modulators. This repurposing drug helps in using these drugs as an adjuvant in tuberculosis, for which the safety is already established through various clinical trials post-marketing surveillance. However, the interaction of these drugs with the standard anti-tubercular drugs and with the disease needs to be studied. In the near future, this host-directed therapy might unlock various management approaches not only in tuberculosis but also in other infective diseases as the action of drugs is on the host.

Stability indicating HPTLC method development and validation for the analysis of novel nitroimidazole antitubercular drug delamanid

Stability indicating HPTLC method development and validation for the analysis of novel nitroimidazole antitubercular drug delamanid