Development Of Antitubercular Drugs Research Articles

Marine-derived Anti-Tuberculosis compounds

Tuberculosis (TB), which is caused primarily by Mycobacterium tuberculosis, is the largest cause of death among all infectious diseases, accounting for more than two million fatalities each year. Marine natural products and some of their derivatives have been found to have potent antitubercular activity against Mycobacterium TB, and some of them have been chosen as prototype molecules for the development of novel anti-tubercular drugs. Because of their strong medicinal qualities, a variety of marine natural products such as terpenoids, alkaloids, pyrones, sterols, and quinones derived from marine sources have piqued interest in recent decades. In this review study, we present current discoveries on the anti-tubercular action of marine natural products, emphasizing their medicinal potential for the treatment of tuberculosis. Based on the research from the last decade, this review provides a full grasp of marine natural products as anti-tubercular agents, as well as a plausible mechanism of action.

Weak links: Advancing target-based drug discovery by identifying the most vulnerable targets.

Mycobacterium tuberculosis remains the most common infectious killer worldwide despite decades of antitubercular drug development. Effectively controlling the tuberculosis (TB) pandemic will require innovation in drug discovery. In this review, we provide a brief overview of the two main approaches to discovering new TB drugs-phenotypic screens and target-based drug discovery-and outline some of the limitations of each method. We then explore recent advances in genetic tools that aim to overcome some of these limitations. In particular, we highlight a novel metric to prioritize essential targets, termed vulnerability. Stratifying targets based on their vulnerability presents new opportunities for future target-based drug discovery campaigns.

Transposon sequencing reveals metabolic pathways essential for Mycobacterium tuberculosis infection.

New drugs are needed to shorten and simplify treatment of tuberculosis caused by Mycobacterium tuberculosis. Metabolic pathways that M. tuberculosis requires for growth or survival during infection represent potential targets for anti-tubercular drug development. Genes and metabolic pathways essential for M. tuberculosis growth in standard laboratory culture conditions have been defined by genome-wide genetic screens. However, whether M. tuberculosis requires these essential genes during infection has not been comprehensively explored because mutant strains cannot be generated using standard methods. Here we show that M. tuberculosis requires the phenylalanine (Phe) and de novo purine and thiamine biosynthetic pathways for mammalian infection. We used a defined collection of M. tuberculosis transposon (Tn) mutants in essential genes, which we generated using a custom nutrient-rich medium, and transposon sequencing (Tn-seq) to identify multiple central metabolic pathways required for fitness in a mouse infection model. We confirmed by individual retesting and complementation that mutations in pheA (Phe biosynthesis) or purF (purine and thiamine biosynthesis) cause death of M. tuberculosis in the absence of nutrient supplementation in vitro and strong attenuation in infected mice. Our findings show that Tn-seq with defined Tn mutant pools can be used to identify M. tuberculosis genes required during mouse lung infection. Our results also demonstrate that M. tuberculosis requires Phe and purine/thiamine biosynthesis for survival in the host, implicating these metabolic pathways as prime targets for the development of new antibiotics to combat tuberculosis.

Unlocking translational machinery for antitubercular drug development

Targeting translational factor proteins presents significant promise for the development of innovative antitubercular drugs. Previous insights from antibiotic binding mechanisms and recently solved 3D crystal structures of Mycobacterium tuberculosis (Mtb) elongation factor thermo unstable–GDP (EF-Tu–GDP), elongation factor thermo stable–EF-Tu (EF-Ts–EF-Tu), and elongation factor G–GDP (EF-G–GDP) have opened up new avenues for the design and development of potent antituberculosis (anti-TB) therapies.

The role of methionine in tuberculosis and its potential clinical significance

Tuberculosis (TB) remains a significant global health challenge. Multidrug-resistant tuberculosis (MDR-TB) holds a substantial health risk, and only a limited number of patients receive treatment for drug-resistant tuberculosis. Various studies have been conducted to address this condition, including through metabolic approaches to further understand the mechanisms of tuberculosis infection, one of which is methionine. There are various enzymes in the Mycobacterium tuberculosis (MTB) methionine biosynthesis pathway, the key enzymes such as MetX, MetC, MetE/MetH, MetK, MTHFR, and BCAT are essential in the biosynthesis of methionine, and hindering these enzyme activities may hold potential for new antitubercular drug development. Deletion of the metA gene weakens MTB, making it more prone to host immune responses. There is also the role of cobalamin, where cobalamin availability regulates the choice between metE and metH in methionine biosynthesis. Methionine plays a crucial role in bacterial protein translation and antioxidant activities. In bacteria including MTB, the initial methionine is formulated; this process involves several enzymes such as FMT, MetRS, PDF, and MetAP. Some compounds targeting MetAP have been identified to have significant inhibitory action against MTB, such as transitmycin and bengamides, and this also includes the drug resistant strain. Methionine supplementation alongside vitamin B-complex have shown to improve drug-induced toxicity in tuberculosis patients, this due to methionine serves as precursor to antioxidant glutathione. Metabolomics studies have shown that altered methionine levels in tuberculosis infection, with samples taken from human blood or urine show significantly lower levels in patients with active TB or failed treatment groups. This review aims to discuss the role of methionine in Mycobacterium tuberculosis and the progress of research targeting methionine metabolism and function.

Identification of new anti-mycobacterial agents based on quinoline-isatin hybrids targeting enoyl acyl carrier protein reductase (InhA)

Tuberculosis (TB) is a global issue that poses a significant economic burden as a result of the ongoing emergence of drug-resistant strains. The urgent requirement for the development of novel antitubercular drugs can be addressed by targeting specific enzymes. One such enzyme, Mycobacterium tuberculosis (MTB) enoyl-acyl carrier protein (enoyl-ACP) reductase (InhA), plays a crucial role in the survival of the MTB bacterium. In this research study, a series of hybrid compounds combining quinolone and isatin were synthesized and assessed for their effectiveness against MTB, as well as their ability to inhibit the activity of the InhA enzyme in this bacterium. Among the compounds tested, 7a and 5g exhibited the most potent inhibitory activity against MTB, with minimum inhibitory concentration (MIC) values of 55 and 62.5 µg/mL, respectively. These compounds were further evaluated for their inhibitory effects on InhA and demonstrated significant activity compared to the reference drug Isoniazid (INH), with IC50 values of 0.35 ± 0.01 and 1.56 ± 0.06 µM, respectively. Molecular docking studies investigated the interactions between compounds 7a and 5g and the target enzyme, revealing hydrophobic contacts with important amino acid residues in the active site. To further confirm the stability of the complexes formed by 5g and 7a with the target enzyme, molecular dynamic simulations were employed, which demonstrated that both compounds 7a and 5g undergo minor structural changes and remain nearly stable throughout the simulated process, as assessed through RMSD, RMSF, and Rg values.

A dual-targeting succinate dehydrogenase and F1Fo-ATP synthase inhibitor rapidly sterilizes replicating and non-replicating Mycobacterium tuberculosis

Mycobacterial bioenergetics is a validated target space for antitubercular drug development. Here, we identify BB2-50F, a 6-substituted 5-(N,N-hexamethylene)amiloride derivative as a potent, multi-targeting bioenergetic inhibitor of Mycobacterium tuberculosis. We show that BB2-50F rapidly sterilizes both replicating and non-replicating cultures of M.tuberculosis and synergizes with several tuberculosis drugs. Target identification experiments, supported by docking studies, showed that BB2-50F targets the membrane-embedded c-ring of the F1Fo-ATP synthase and the catalytic subunit (substrate-binding site) of succinate dehydrogenase. Biochemical assays and metabolomic profiling showed that BB2-50F inhibits succinate oxidation, decreases the activity of the tricarboxylic acid (TCA) cycle, and results in succinate secretion from M.tuberculosis. Moreover, we show that the lethality of BB2-50F under aerobic conditions involves the accumulation of reactive oxygen species. Overall, this study identifies BB2-50F as an effective inhibitor of M.tuberculosis and highlights that targeting multiple components of the mycobacterial respiratory chain can produce fast-acting antimicrobials.

Mycobacterial FtsZ and inhibitors: a promising target for the anti-tubercular drug development.

The emergence of multidrug-resistant tuberculosis (MDR-TB) strains has rendered many anti-TB drugs ineffective. Consequently, there is an urgent need to identify new drug targets against Mycobacterium tuberculosis (Mtb). Filament Forming Temperature Sensitive Gene Z (FtsZ), a member of the cytoskeletal protein family, plays a vital role in cell division by forming a cytokinetic ring at the cell's center and coordinating the division machinery. When FtsZ is depleted, cells are unable to divide and instead elongate into filamentous structures that eventually undergo lysis. Since the inactivation of FtsZ or alterations in its assembly impede the formation of the Z-ring and septum, FtsZ shows promise as a target for the development of anti-mycobacterial drugs. This review not only discusses the potential role of FtsZ as a promising pharmacological target for anti-tuberculosis therapies but also explores the structural and functional aspects of the mycobacterial protein FtsZ in cell division. Additionally, it reviews various inhibitors of Mtb FtsZ. By understanding the importance of FtsZ in cell division, researchers can explore strategies to disrupt its function, impeding the growth and proliferation of Mtb. Furthermore, the investigation of different inhibitors that target Mtb FtsZ expands the potential for developing effective treatments against tuberculosis.

Flavonoids of Chromolaena odorata (L.) R.M.King & H.Rob. as potential leads for treatment against tuberculosis

Tuberculosis (TB) is currently rated as the 13th leading cause of mortality and the second leading cause of death after COVID-19, and above AIDS. Existing challenges relating to the development of multidrug-resistant strains and dangerous side effects of currently used drugs add impetus to the search for additional TB treatments. Hence, interest has grown in the use of medicinal plants as a source of bioactive preparations with efficacy against TB-causing organisms, and also with the ability to ameliorate the negative effects of TB drugs. This study aimed to evaluate the antimycobacterial and hepatoprotective potentials of extracts and isolated flavonoid compounds from invasive Chromolaena odorata. Test organisms used were pathogenic Mycobacterium bovis and M. tuberculosis H37RV, and the fast-growing M. aurum, M. fortuitum and M. smegmatis. The selectivity index (SI) values of the test substances were determined through cytotoxicity assays to promote these extracts and compounds as leads for the development of effective and safe anti-tubercular drugs. The antimycobacterial activity was evaluated using a serial microdilution method, and the SI was calculated from the 50% lethal concentrations calculated from cytotoxicity tests. Hepatoprotective activity was determined using HepG2 liver cells treated with rifampicin as a toxin. The extracts and compounds had a range of antimycobacterial activity with minimum inhibitory concentration (MIC) values ranging from 0.031 to 2.5 mg/mL. Two flavonoid compounds, 5,7,4′-trimethoxy flavanone and 5‑hydroxy-3,7,4′-trimethoxyflavone showed promising antimycobacterial potential, and minimal toxicity was observed, as most SI values were higher than 1. The flavonoid compound 5,7,4′-trimethoxy flavanone had the highest SI (6.452), which was against M. tuberculosis H37RV. The HepG2 cells were reduced to 65% due to toxicity by rifampicin, however, the flavonoid compounds were able to improve cell viability to between 81 and 89% at different concentrations tested. Results obtained indicate that C. odorata may serve as a lead for the development of safe and effective antimycobacterial and hepatoprotective drugs.

Proximity-dependent biotin identification links cholesterol catabolism with branched-chain amino acid degradation in Mycobacterium smegmatis.

Cholesterol is a crucial component in Mycobacterium tuberculosis virulence as it is required for phagocytosis of mycobacteria by macrophages. In addition, the tubercle bacilli can grow using cholesterol as the sole carbon source. Thus, cholesterol catabolism represents a valuable target for the development of new antitubercular drugs. However, the molecular partners of cholesterol catabolism remain elusive in mycobacteria. Here, we focused on HsaC and HsaD, enzymes involved in two consecutive steps of cholesterol ring degradation and identified putative partners, using a BirA-based proximity-dependent biotin identification (BioID) approach in Mycobacterium smegmatis. In rich medium, the fusion protein BirA-HsaD was able to fish the endogenous cognate HsaC, thus validating this approach to study protein-protein interactions and to infer metabolic channeling of cholesterol ring degradation. In chemically defined medium, both HsaC and HsaD interacted with four proteins, BkdA, BkdB, BkdC, and MSMEG_1634. BkdA, BkdB, and BkdC are enzymes that participate in the degradation of branched-chain amino acids. As cholesterol and branched-chain amino acid catabolism both generate propionyl-CoA, which is a toxic metabolite for mycobacteria, this interconnection suggests a compartmentalization to avoid dissemination of propionyl-CoA into the mycobacterial cytosol. Moreover, the BioID approach allowed us to decipher the interactome of MSMEG_1634 and MSMEG_6518, two proteins of unknown function, which are proximal to the enzymes involved in cholesterol and branched-chain amino acid catabolism. In conclusion, BioID is a powerful tool to characterize protein-protein interactions and to decipher the interconnections between different metabolic pathways, thereby facilitating the identification of new mycobacterial targets.

Isatin-pyrimidine hybrid derivatives as enoyl acyl carrier protein reductase (InhA) inhibitors against Mycobacterium tuberculosis

Tuberculosis is a worldwide problem that impose a burden on the economy due to continuous development of resistant strains. The development of new antitubercular drugs is a need and can be achieved through inhibition of druggable targets. Mycobacterium tuberculosis enoyl acyl carrier protein (ACP) reductase (InhA) is an important enzyme for Mycobacterium tuberculosis survival. In this study, we report the synthesis of isatin derivatives that could treat TB through inhibition of this enzyme. Compound 4l showed IC50 value (0.6 ± 0.94 µM) similar to isoniazid but is also effective against MDR and XDR Mycobacterium tuberculosis strains (MIC of 0.48 and 3.9 µg/mL, respectively). Molecular docking studies suggest that this compound binds through the use of relatively unexplored hydrophobic pocket in the active site. Molecular dynamics was used to investigate and support the stability of 4l complex with the target enzyme. This study paves the way for the design and synthesis of novel antitubercular drugs.

Novel Benzylamine Derivatives: Synthesis, Anti-Mycobacterium Tuberculosis Evaluation and Predicted ADMET Properties

Background: Tuberculosis (TB), a disease caused by the bacillus bacteria Mycobacterium tuberculosis is one of the major contributors of ill health in the world. TB is ranked in the top 10 causes of death globally and it is the leading killer associated with a single infectious agent. According to the World Health Organization (WHO), global number of deaths associated with TB have been slowly declining with 1.3 million in reported 2016 and 2017, and 1.2 million reported in 2018 and 2019. Objective: The synthesis, characterisation, biological evaluations, and the prediction of ADMET properties of the novel benzylamine derivatives. Methods: Commercially available reagents and solvents were purchased from Sigma Aldrich and Merck (South Africa). All chemicals were used as received, unless otherwise stated. The synthesised crude compounds were purified by flash silica gel column chromatography (5 – 30% ethyl acetate in hexane). The successful formation and purity of the synthesised compounds was confirmed by NMR, HRMS and melting point. Results: The respective organic compounds were synthesised by treating 3-ethoxysalcyladehyde, 5-bromo-3-ethoxysalcyladehyde, 5-chloro-3-ethoxysalcyladehyde with various aromatic amines and the products were obtained in good to excellent yields. The 1H and 13C NMR spectra of all the products showed the appearance of the methylene signals ranging from 3.88 – 4.68 ppm and 42.25 – 52.57 ppm respectively. Additionally, most compounds showed anti-Mycobacterium tuberculosis activity that ranged between 20 and 28 µM. Conclusion: A total of 36 compounds were synthesised and successfully biologically evaluated against Mycobacterium tuberculosis (Mtb) H37RV strain. All compounds showed activity against Mtb at concentrations of > 20 µM < 28 µM with the exception of compound one that was active against Mtb at higher concentration (MIC90 > 125 µM).

Identification of bioactive compounds Inhibitors of M. tuberculosis Growth Using Whole Cell Based High-Throughput Screening

Drug discovery and development for Mycobacterium tuberculosis (Mtb) has progressed significantly in more than 20 years, although it is still woefully underfunded. From a drug discovery perspective, tuberculosis is a particularly challenging disease. Screening for new antimicrobial agents is routinely conducted only against actively replicating bacteria. However, it is now widely accepted that a physiological state of nonreplicating persistence (NRP) is responsible for antimicrobial tolerance in many bacterial infections. The MICs of 138 established pure bioactive compounds determined in microplate cultures, of which anaerobic conditions were maintained for ten days and, for comparative purposes, aerobic conditions for seven days. Cultures exposed to drugs under anaerobic conditions followed by 28h of “recovery” under ambient oxygen produced a luminescent signal that was, for most compounds, proportional to the number of hits determined > 90% in MICs MABA was 99 (71.7%), GAS was 118 (85.5%), and MICs LORA was 7 (5.1%). As a result, aerobic and anaerobic bacteria conditions in vitro assays are prone to support a drug discovery program for tuberculosis. These potential bioactive compounds are in the drug discovery and development of anti-tubercular drugs.

Design, Synthesis and Anti-tubercular Evaluation of Some Novel Chroman-Hydrazone Derivatives

The molecular docking, synthesis, spectral characterization and anti-tubercular evaluation of 10 novel N’-substituted-6-hydroxy-2,5,7,8-tetramethylchroman-2-carbohydrazide derivatives (SM1-SM10) were reported. The structures of the synthesized derivatives were affirmed by spectroscopic studies such as FTIR, 1H NMR, 13C NMR and high resolution-mass spectrometry. Predicted ADME and toxicity investigations were accomplished to presume the pharmacokinetic parameters of the compounds. The synthesized compounds were evaluated for in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain using Microplate Alamar Blue Assay (MABA) taking isoniazid, rifampicin, ethambutol, amikacin, streptomycin and levofloxacin as positive drug standards. Compound SM8 has shown the significant anti-tubercular activity among all the titled compounds. The results indicated that chroman-hydrazone skeleton could serve as a lead for the development of novel anti-tubercular drugs.

Structural Basis of Cysteine Ligase MshC Inhibition by Cysteinyl-Sulfonamides

Mycothiol (MSH), the major cellular thiol in Mycobacterium tuberculosis (Mtb), plays an essential role in the resistance of Mtb to various antibiotics and oxidative stresses. MshC catalyzes the ATP-dependent ligation of 1-O-(2-amino-2-deoxy-α-d-glucopyranosyl)-d-myo-inositol (GlcN-Ins) with l-cysteine (l-Cys) to form l-Cys-GlcN-Ins, the penultimate step in MSH biosynthesis. The inhibition of MshC is lethal to Mtb. In the present study, five new cysteinyl-sulfonamides were synthesized, and their binding affinity with MshC was evaluated using a thermal shift assay. Two of them bind the target with EC50 values of 219 and 231 µM. Crystal structures of full-length MshC in complex with these two compounds showed that they were bound in the catalytic site of MshC, inducing dramatic conformational changes of the catalytic site compared to the apo form. In particular, the observed closure of the KMSKS loop was not detected in the published cysteinyl-sulfamoyl adenosine-bound structure, the latter likely due to trypsin treatment. Despite the confirmed binding to MshC, the compounds did not suppress Mtb culture growth, which might be explained by the lack of adequate cellular uptake. Taken together, these novel cysteinyl-sulfonamide MshC inhibitors and newly reported full-length apo and ligand-bound MshC structures provide a promising starting point for the further development of novel anti-tubercular drugs targeting MshC.

M. tuberculosis Transcription Machinery: A Review on the Mycobacterial RNA Polymerase and Drug Discovery Efforts.

Mycobacterium tuberculosis (MTB) is the main source of tuberculosis (TB), one of the oldest known diseases in the human population. Despite the drug discovery efforts of past decades, TB is still one of the leading causes of mortality and claimed more than 1.5 million lives worldwide in 2020. Due to the emergence of drug-resistant strains and patient non-compliance during treatments, there is a pressing need to find alternative therapeutic agents for TB. One of the important areas for developing new treatments is in the inhibition of the transcription step of gene expression; it is the first step to synthesize a copy of the genetic material in the form of mRNA. This further translates to functional protein synthesis, which is crucial for the bacteria living processes. MTB contains a bacterial DNA-dependent RNA polymerase (RNAP), which is the key enzyme for the transcription process. MTB RNAP has been targeted for designing and developing antitubercular agents because gene transcription is essential for the mycobacteria survival. Initiation, elongation, and termination are the three important sequential steps in the transcription process. Each step is complex and highly regulated, involving multiple transcription factors. This review is focused on the MTB transcription machinery, especially in the nature of MTB RNAP as the main enzyme that is regulated by transcription factors. The mechanism and conformational dynamics that occur during transcription are discussed and summarized. Finally, the current progress on MTB transcription inhibition and possible drug target in mycobacterial RNAP are also described to provide insight for future antitubercular drug design and development.

Novel diaryl ether derivatives as InhA inhibitors: Design, synthesis and antimycobacterial activity

A new series of triclosan (TCL)-mimicking diaryl ether derivatives 7–25 were synthesized and evaluated as inhibitors of enoyl acyl carrier protein reductase InhA enzyme. In addition, these derivatives were screened as inhibitors of drug-susceptible (DS), multidrug-resistant (MDR), and extensive drug-resistant (XDR) Mycobacterium tuberculosis (MTB) strains. Most compounds exihibted superior anti-TB activities and improved ClogP compared to TCL as a standard drug. The present work has led to the identification of compounds 14, 19 and 24 which possess remarkable activities against DS, MDR and XDR MTB strains with MIC values of 1.95, 3.9 and 15.63 µg/ml, respectively for compound 14, 1.95, 3.9 and 7.81 µg/ml, respectively for compound 19 and 0.98, 1.95 and 3.9 µg/ml, respectively for compound 24. Most compounds did not exhibit toxicity to HePG2 normal cell line. Compounds 14, 19 and 24, presenting the best MIC values, were further evaluated as inhibitors of InhA enzyme. They showed high binding affinities in the micromolar range with IC50 values of 1.33, 0.6, and 0.29 µM for compounds 14, 19, and 24, respectively. Furthermore, molecular docking approach was utilized to understand the difference in bioactivities between the new compounds. In particular, the results revealed strong binding interactions and high docking scores of compounds 14, 19 and 24, which could correlate with their high activities. Mainly, the molecular modelling study of compound 24 provides an excellent platform for understanding the molecular mechanism regarding InhA inhibition. Thus, compound 24 could be a lead compound for future development of new antitubercular drugs.

Synthesis and antimycobacterial evaluation of pyrazinamide, benzimidazole and carboxamide derivatives

AbstractDue to the unusual structure and chemical composition of the mycobacterial cell wall, it is difficult to develop effective antitubercular treatment as it leads to many antibiotics not working and preventing drug entry. It also leads to the problem of more drug resistance. Tuberculosis (TB) is still the second most contagious disease with about 33% of the world's population being affected mainly by drug‐resistant TB (MDR, XDR), chronic infections, and the combination of TB and human immunodeficiency virus (HIV). Therefore, there is an urgent need for the development of novel antitubercular drugs that will shorten the total duration of effective treatment taken under directly observed treatment, short‐course (DOTS) guidance, solve the problem of multiple drug resistance, and provide effective treatment for TB diseases. In this review, we considered various synthetic schemes of pyrazinamide, benzimidazole, and carboxamide derivatives that have antitubercular properties that can overcome the resistance to parental drugs and thus act as an effective alternative.

Antitubercular activity assessment of fluorinated chalcones, 2-aminopyridine-3-carbonitrile and 2-amino-4H-pyran-3-carbonitrile derivatives: In vitro, molecular docking and in-silico drug likeliness studies.

A series of newer previously synthesized fluorinated chalcones and their 2-amino-pyridine-3-carbonitrile and 2-amino-4H-pyran-3-carbonitrile derivatives were screened for their in vitro antitubercular activity and in silico methods. Compound 40 (MIC~ 8 μM) was the most potent among all 60 compounds, whose potency is comparable with broad spectrum antibiotics like ciprofloxacin and streptomycin and three times more potent than pyrazinamide. Additionally, compound 40 was also less selective and hence non-toxic towards the human live cell lines-LO2 in its MTT assay. Compounds 30, 27, 50, 41, 51, and 60 have exhibited streptomycin like activity (MIC~16-18 μM). Fluorinated chalcones, pyridine and pyran derivatives were found to occupy prime position in thymidylate kinase enzymatic pockets in molecular docking studies. The molecule 40 being most potent had shown a binding energy of -9.67 Kcal/mol, while docking against thymidylate kinase, which was compared with its in vitro MIC value (~8 μM). These findings suggest that 2-aminopyridine-3-carbonitrile and 2-amino-4H-pyran-3-carbonitrile derivatives are prospective lead molecules for the development of novel antitubercular drugs.

Synthesis, antimicrobial, and antitubercular evaluation of new Schiff bases with in silico ADMET and molecular docking studies

Schiff bases are a proven moiety in antitubercular drug discovery and the antitubercular drug development. Drug discovery is a never-ending process due to evolving drug resistance by the bacteria, as a result, there is a need of developing new antitubercular drugs. In this continuous process of antitubercular drug discovery, new series of Schiff bases are synthesized using quinoline carbohydrazide upon coupling with different aldehydes in ethanolic media through multistep synthesis. These synthesized compounds were purified and characterized by different spectroscopic techniques. The molecules were in vitro screened for antifungal and antibacterial potential by Agar well diffusion assay, antitubercular activity by using microplate Alamar blue assay, and an attempt has been made to study the in-silico relationship between new Schiff base derivatives 4a-f and the crystal structure of M. tuberculosis (5V3Y) protein by molecular docking studies. Synthesized compounds 4a-f show good interaction with the crystal structure of M. tuberculosis protein (5V3Y) and fulfill ADMET characteristics in silico experiments. Among the compounds tested, compound 4d was found to be active against bacteria and fungi. Compound 4b was found to be sensitive against M. tuberculosis at 50 µg/mL concentration.