Potential anti-TB Drug Research Articles

A new N-acylhydrazone oxadiazole derivative with activity against mycobacteria.

Aim: To evaluate the anti-Mycobacterium tuberculosis (Mtb) potential of the hybrid oxadiazol-4-methoxynaphthalene (6n) derived from N-acylhydrazone (4k).Materials & methods: The study determined the minimal inhibitory concentration of (6n) against Mtb H37Rv and Mtb clinical isolates, potential combination of (6n) with anti-tuberculosis drugs and carried out time kill curve assay of Mtb H37Rv. Additional contribution for the analysis of (6n) was explored by in silico pharmacokinetics, and in vitro and in vivo cytotoxicity determinations.Results: The newly synthesized molecule (6n) demonstrated anti-Mtb activity, low cytotoxicity and selectivity for Mtb.Conclusion: The derivative (6n) emerges as a potential anti-TB drug candidate.

Computational analysis of RNA methyltransferase Rv3366 as a potential drug target for combating drug-resistant Mycobacterium tuberculosis.

Mycobacterium tuberculosis (M.tb) remains a formidable global health threat. The increasing drug resistance among M.tb clinical isolates is exacerbating the current tuberculosis (TB) burden. In this study we focused on identifying novel repurposed drugs that could be further investigated as potential anti-TB drugs. We utilized M.tb RNA methyltransferase Rv3366 (spoU) as a potential drug target due to its imperative activity in RNA modification and no structural homology with human proteins. Using computational modeling approaches the structure of Rv3366 was determined followed by high throughput virtual screening of Food and Drug Administration (FDA) approved drugs to screen potential binders of Rv3366. Molecular dynamics (MD) simulations were performed to assess the drug-protein binding interactions, complex stability and rigidity. Through this multi-step structure-based drug repurposing workflow two promising inhibitors of Rv3366 were identified, namely, Levodopa and Droxidopa. This study highlights the significance of targeting M.tb RNA methyltransferases to combat drug-resistant M.tb. and proposes Levodopa and Droxidopa as promising inhibitors of Rv3366 for future pre-clinical investigations.

State-of-the-art strategies to prioritize Mycobacterium tuberculosis drug targets for drug discovery using a subtractive genomics approach

Tuberculosis remains one of the causes of death from a single infectious bacterium. The inappropriate use of antibiotics and patients’ non-compliance among other factors drive the emergence of drug-resistant tuberculosis. Multidrug-resistant and extensively drug-resistant strains of tuberculosis pose significant challenges to current treatment regimens, as their reduced efficacy against these strains limits successful patient outcomes. Furthermore, the limited effectiveness and associated toxicity of second-line drugs further compound the issue. Moreover, the scarcity of novel pharmacological targets and the subsequent decline in the number of anti-TB compounds in the drug development pipeline has further hindered the emergence of new therapies. As a result, researchers need to develop innovative approaches to identify potential new anti-TB drugs. The evolution of technology and the breakthrough in omics data allow the use of computational biology approaches, for example, metabolomic analysis to uncover pharmacological targets for structured-based drug design. The role of metabolism in pathogen development, growth, survival, and infection has been established. Therefore, this review focuses on the M. tb metabolic network as a hub for novel target identification and highlights a step-by-step subtractive genomics approach for target prioritization.

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.

Structural insight into mycobacterial cell wall biosynthesis by AftB, a potential anti-TB drug target.

Tuberculosis (TB) is a severe infectious disease caused by Mycobacterium tuberculosis (Mtb) and remains a significant health problem worldwide. The success of Mtb as the leading pathogen can largely be attributed to its atypical multilayered cell wall, which is highly impermeable and confers natural protection against attack from the immune system and many antibiotics. Due to its unique character, the mycobacterial cell wall has become the most widely exploited target of anti-TB drugs. AftB is an arabinofuranosyltransferase that functions in the terminal step of cell wall arabinan biosynthesis, catalyzing the transfer of arabinose from the donor decaprenyl-phosphate-arabinose (DPA) onto the cell wall polysaccharides. AftB is essential for Mtb's survival and is deemed a potential new drug target for TB. Here we report the atomic-resolution structures of AftB obtained by cryo-EM in both apo and donor substrate analog bound forms. The apo structure revealed that AftB contains 11 transmembrane helices belonging to the GT-C glycosyltransferase superfamily and a periplasmic segment of a novel fold which might direct the binding of polysaccharides acceptor. AftB forms a large putative substrate-binding cavity, with one side facing the periplasmic domain and the other facing the lipid bilayer. The substrate-bound structure further unmasked the nature of the active site. Using synthetic AftB donor and acceptor substrates, we recapitulated the enzymatic reaction in vitro. And the functional analysis using AftB variants further proved the importance of the active site revealed from our structures. We proposed that AftB catalyzes the glycosylation reaction by utilizing a conserved aspartate residue as the base catalyst. Collectively, our work provides a structural basis for understanding the molecular mechanism of AftB and a blueprint for developing new drugs to combat the increasing threat caused by Mtb.

Combined Bioinformatics and Combinatorial Chemistry Tools to Locate Drug-Able Anti-TB Phytochemicals: A Cost-Effective Platform for Natural Product-Based Drug Discovery.

Based on extensive experimental studies, a huge number of phytochemicals showed potential activity against tuberculosis (TB) at a lower minimum inhibitory concentration (MIC) and fewer toxicity profiles. However, these promising drugs have not been able to convert from 'lead' to 'mainstream' due to inadequate drug-ability profiles. Thus, early drug-prospective analyses are required at the primary stage to accelerate natural-product-based drug discovery with limited resources and time. In the present study, we have selected seventy-three potential anti-TB phytochemicals (MIC value ≤10 μg/mL) and assessed the drug-ability profiles using bioinformatics and combinatorial chemistry tools, systematically. Primarily, the molecular docking study was done against two putative drug targets, catalase-peroxidase enzyme (katG) and RNA polymerase subunit-β (rpoB) of Mycobacterium tuberculosis (Mtb) using AutoDock 4.2 software. Further, assessed the drug-ability score from Molsoft, toxicity profiles from ProTox, pharmacokinetics from SwisADME, hierarchical cluster analysis (HCA) by ChemMine tools and frontier molecular orbitals (FMOs) with Avogadro and structural activity relationships (SAR) analysis with ChemDraw 18.0 software. Above analyses indicated that, lower MIC exhibited anti-TB phytochemicals, abietane, 12-demethylmulticaulin exhibited poor docking and drug-ability scores, while tiliacorinine, 2-nortiliacorinine showed higher binding energy and drug-ability profiles. Overall, tiliacorinine, 2-nortiliacorinine, 7α-acetoxy-6β-hydroxyroyleanone (AHR), (2S)-naringenin and isovachhalcone were found as the most active and drug-able anti-TB candidates from 73 candidates. Phytochemicals are always a vital source of mainstream drugs, but the MIC value of a phytochemical is not sufficient for it to be promoted. An ideal drug-ability profile is therefore essential for achieving clinical success, where advanced bioinformatics tools help to assess and analyse that profile. Additionally, several natural pharmacophores found in existing anti-TB drugs in SAR analyses also provide crucial information for developing potential anti-TB drug. As a conclusion, combined bioinformatics and combinatorial chemistry are the most effective strategies to locate potent-cum-drug-able candidates in the current drug-development module.

Mycobacterium tuberculosis and Pulmonary Rehabilitation: From Novel Pharmacotherapeutic Approaches to Management of Post-Tuberculosis Sequelae.

Tuberculosis (TB) is still a worldwide public health burden, as more than 1.3 million deaths are expected to be reported in 2021. Even though almost 20 million patients have completed specific anti-TB treatment and survived in 2020, little information is known regarding their pulmonary sequelae, quality of life, and their need to follow rehabilitation services as researchers shifted towards proper diagnosis and treatment rather than analyzing post-disease development. Understanding the underlying immunologic and pathogenic mechanisms during mycobacterial infection, which have been incompletely elucidated until now, and the development of novel anti-TB agents could lead to the proper application of rehabilitation care, as TB sequelae result from interaction between the host and Mycobacterium tuberculosis. This review addresses the importance of host immune responses in TB and novel potential anti-TB drugs’ mechanisms, as well as the assessment of risk factors for post-TB disease and usefulness of guidance and optimization of pulmonary rehabilitation. The use of rehabilitation programs for patients who successfully completed anti-tuberculotic treatment represents a potent multifaceted measure in preventing the increase of mortality rates, as researchers conclude that a patient with a TB diagnosis, even when properly completing pharmacotherapy, is threatened by a potential life loss of 4 years, in comparison to healthy individuals. Dissemination of pulmonary rehabilitation services and constant actualization of protocols could strengthen management of post-TB disease among under-resourced individuals.

Medium optimization and subsequent fermentative regulation enabled the scaled-up production of anti-tuberculosis drug leads ilamycin-E1/E2.

Tuberculosis (TB) and its evolving drug resistance have exerted severe threats on the global health, hence it is still essential to develop novel anti-TB antibiotics. Ilamycin-E1/E2 is a pair of cycloheptapeptide enantiomers obtained from a marine Streptomyces atratus SCSIO ZH16-ΔilaR mutant, and has presented significant anti-TB activities as promising drug lead compounds, but their clinical development has been hampered by low fermentation titers. By applying the statistical Plackett-Burman design (PBD) model, bacterial peptone was first screened out as the only significant but negative factor to affect the ilamycin-E1/E2 production. Subsequent single factor optimization in shaking flasks revealed that the replacement of bacterial peptone with malt extract could not only eliminate the accumulation of porphyrin-type competitive byproducts but also improve the titer of ilamycin-E1/E2 from original 13.6±0.8 to 142.7±5.7mgL-1 , about 10.5-fold increase. Next, a pH coordinated feeding strategy was adopted in 30L fermentor and obtained 169.8±2.5mgL-1 ilamycin-E1/E2, but further scaled-up production in 300L fermentor only gave a titer of 131.5±7.5mgL-1 due to the unsynchronization of feeding response and pH change. Consequently, a continuous pulse feeding strategy was utilized in 300L fermentor to solve the above problem and finally achieved 415.7±29.2mgL-1 ilamycin-E1/E2, representing a 30.5-fold improvement. Our work has provided a solid basis to acquire sufficient ilamycin-E1/E2 lead compounds and then support their potential anti-TB drug development.

Potential anti-TB investigational compounds and drugs with repurposing potential in TB therapy: a conspectus.

The latest WHO report estimates about 1.6 million global deaths annually from TB, which is further exacerbated by drug-resistant (DR) TB and comorbidities with diabetes and HIV. Exiguous dosing, incomplete treatment course, and the ability of the tuberculosis bacilli to tolerate and survive current first-line and second-line anti-TB drugs, in either their latent state or active state, has resulted in an increased prevalence of multidrug-resistant (MDR), extensively drug-resistant (XDR), and totally drug-resistant TB (TDR-TB). Although a better understanding of the TB microanatomy, genome, transcriptome, proteome, and metabolome, has resulted in the discovery of a few novel promising anti-TB drug targets and diagnostic biomarkers of late, no new anti-TB drug candidates have been approved for routine therapy in over 50years, with only bedaquiline, delamanid, and pretomanid recently receiving tentative regulatory approval. Considering this, alternative approaches for identifying possible new anti-TB drug candidates, for effectively eradicating both replicating and non-replicating Mycobacterium tuberculosis, are still urgently required. Subsequently, several antibiotic and non-antibiotic drugs with known treatment indications (TB targeted and non-TB targeted) are now being repurposed and/or derivatized as novel antibiotics for possible use in TB therapy. Insights gathered here reveal that more studies focused on drug-drug interactions between licensed and potential lead anti-TB drug candidates need to be prioritized. This write-up encapsulates the most recent findings regarding investigational compounds with promising anti-TB potential and drugs with repurposing potential in TB therapy.

Antimycobacterial Rufomycin Analogues from Streptomyces atratus Strain MJM3502.

This study represents a systematic chemical and biological study of the rufomycin (RUF) class of cyclic heptapeptides, which our anti-TB drug discovery efforts have identified as potentially promising anti-TB agents that newly target the caseinolytic protein C1, ClpC1. Eight new RUF analogues, rufomycins NBZ1-NBZ8 (1-8), as well as five known peptides (9-13) were isolated and characterized from the Streptomyces atratus strain MJM3502. Advanced Marfey's and X-ray crystallographic analysis led to the assignment of the absolute configuration of the RUFs. Several isolates exhibited potent activity against both pathogens M. tuberculosis H37Rv and M. abscessus, paired with favorable selectivity (selectivity index >60), which collectively underscores the promise of the rufomycins as potential anti-TB drug leads.

Opportunities and challenges of using five-membered ring compounds as promising antitubercular agents.

Tuberculosis (TB), a chronic infectious disease, is one of the greatest risks to human beings and 10 million people were diagnosed with TB and 1.6 million died from this disease in 2017. In addition, with the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), the TB situation has become even worse, which has aggravated the mortality and spread of this disease. To overcome this problem, research into novel antituberculosis agents with enhanced activities against MDR-TB, reduced toxicity, and shortened duration of therapy is of great importance. Fortunately, many novel potential anti-TB drug candidates with five-membered rings, which are most likely to be effective against sensitive and resistant strains, have recently entered clinical trials. Different five-membered rings such as furans, pyranoses, thiazoles, pyrazolines, imidazoles, oxazolidinone, thiazolidins, isoxazoles, triazoles, oxadiazoles, thiadiazoles, and tetrazoles have been designed, prepared, and evaluated for their antimycobacterial activity against Mycobacterium tuberculosis. In this article, we highlight the recent advances made in the discovery of novel five-membered ring compounds and focus on their antitubercular activities, toxicity, structure-activity relationships, and mechanisms of action.

Design, Synthesis, Characterisation and Biological Evaluation of some Novel 1, 3, 4 Thiadiazole Derivatives as Anti-tubercular agents Targeting Decaprenyl Phosphoryl Beta-D-Ribose 2 ’Epimerase-1

INTRODUCTION:Tuberculosis [TB] is caused by mycobacterium tuberculosis that most often affect the lungs. Tuberculosis is curable and preventable. In 1882, the German physician Robert Koch isolated the bacterium. Tuberculosis is contagious and airborne disease. In 1944, streptomycin was to treat tuberculosis [TB]. This amino glycoside interferes with protein biosynthesis through an interaction with the small 30s subunit of the ribosome. The discovery of Para amino salicylic acid in 1946 was quickly followed by the important discovery of Isoniazid [INH], as one of the most active anti-TB drugs used today. Inhibition of mycolic acids biosynthesis, one of the essential components of the mycobacterium cell wall was determined as the mechanism of action. Pyrazinamide [PZA] appeared as a potential Anti-TB drug in 1952. The TB treatment in the 1980s was a great success as it allowed to shorten the duration of the therapy from 9 to 6 months. Ethambutol [EMB] and Rifampin [RIF], the two last derivatives used in the TB first-line treatment, were discovered during the 60s. Ethambutol is an ethylenediamine discovered in 1961, which affects the cell wall by specifically targeting the polymerization of arabinogalactan and lipoarabinomannan. Finally, Rifampin appeared as a drug of choice for TB treatment around 1970, by acting on replicating and non-replicating mycobacteria. This derivative belongs to the rifampicin family and inhibits bacterial RNA synthesis by binding to the b-subunit of the DNA-dependent polymerase. AIM: The aim of this project is to design molecules with potential anti-tubercular activity that is capable of inhibiting cell wall synthesis by inhibiting Decaprenylphosphoryl-beta-D-ribose2-epimerase-1. The designed compounds will be synthesized, characterized and evaluated for biological activity and toxicity. OBJECTIVE:The compounds are designed and docked against a specific crucial target, Decaprenylphosphoryl-beta-D-ribose2epimerase-1.This is involved in the cell wall biosynthesis and Lipid metabolism. The synthesized compounds are expected to act on the same.SUMMARY:Decaprenylphosphoryl-beta-D-ribose 2-epimerase a critical enzyme for the growth of Mycobacterium tuberculosis was chosen for our study after review of literature. It belongs to the Oxidoreductase family. A database of 200 molecules with high prospects of inhibiting the target Dpre1 were carefully chosen by making changes to the known hit molecules, here the thiadiazole nucleus was chosen. Selected molecules were designed and docked against Dpre1 using Argus lab® software. Six molecules with good docking score [lower binding energy] and interactions were shortlisted for synthesis. Reaction conditions were optimized. The selected molecules were subjected to toxicity prediction assessment by OSIRIS® property explorer developed by Acetilon Pharmaceuticals limited which is available online. The results are color coded as green color which predicts the drug likeness and possibly better activity. The molecules were labelled as SDK1, SDK2, SDK3, SDK5, PAA, HA, and were synthesized with satisfactory yield. The purity of the synthesized compounds was ensured by repeated recrystallization. Further the compounds were evaluated by TLC and Melting point determination. The characterization of the synthesized compounds was done using Infra-red, Nuclear Magnetic Resonance [H1 NMR] and Mass spectrometric methods [LC-MS, GC-MS]. All the Synthesized compounds exhibited molecular ion peak (M+) of varying intensities. The final pure compounds were screened for Anti-mycobacterial activity by in vitro method called Micro plate Alamar Blue Assay [MABA]. The synthesized compounds showed sensitivity [Minimum inhibitory concentration] at 3.12mcg/ml. The standard drugs Pyrazinamide, Streptomycin, Ciprofloxacin exhibited anti mycobacterial activity at 3.125mcg/ml, 6.25mcg/ml, and 3.125mcg/ml concentrations respectively. This indicates that the synthesized compounds are as Potent as the standard drugs.CONCLUSION:All the compounds gave Docking score between -8.73 to 11.37 kcal/mol Pyrazinamide gave docking score 11.55kcal/mol for 4P8Y, Streptomycin gave docking score of 10.87kcal/mol for 4P8Y and Ciprofloxacin gave docking score of 11.25kcal/mol for 4P8Y. There is a correlation between the score and activities of all the compounds which were tested and compared with the standard drugs. This goes to prove that Decaprenyl phosphoryl beta-D-ribose 2’ epimerase-1’ (PDBID: 4P8Y) is a critical enzyme for anti-mycobacterial activity. So the fine tuning the structures of these compounds will yield molecules with better anti mycobacterial activity. Further structural modifications of the synthesized compounds will aid in the development of potential molecules against the tuberculosis pathogen.

Ureidopyrazine Derivatives: Synthesis and Biological Evaluation as Anti-Infectives and Abiotic Elicitors.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) has become a frequently deadly infection due to increasing antimicrobial resistance. This serious issue has driven efforts worldwide to discover new drugs effective against Mtb. One research area is the synthesis and evaluation of pyrazinamide derivatives as potential anti-TB drugs. In this paper we report the synthesis and biological evaluations of a series of ureidopyrazines. Compounds were synthesized by reacting alkyl/aryl isocyanates with aminopyrazine or with propyl 5-aminopyrazine-2-carboxylate. Reactions were performed in pressurized vials using a CEM Discover microwave reactor with a focused field. Purity and chemical structures of products were assessed, and the final compounds were tested in vitro for their antimycobacterial, antibacterial, and antifungal activities. Propyl 5-(3-phenylureido)pyrazine-2-carboxylate (compound 4, MICMtb = 1.56 μg/mL, 5.19 μM) and propyl 5-(3-(4-methoxyphenyl)ureido)pyrazine-2-carboxylate (compound 6, MICMtb = 6.25 μg/mL, 18.91 μM) had high antimycobacterial activity against Mtb H37Rv with no in vitro cytotoxicity on HepG2 cell line. Therefore 4 and 6 are suitable for further structural modifications that might improve their biological activity and physicochemical properties. Based on the structural similarity to 1-(2-chloropyridin-4-yl)-3-phenylurea, a known plant growth regulator, two selected compounds were evaluated for similar activity as abiotic elicitors.

In silico approaches and chemical space of anti-P-type ATPase compounds for discovering new antituberculous drugs.

Tuberculosis (TB) is one of the most important public health problems around the world. The emergence of multi-drug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis strains has driven the finding of alternative anti-TB targets. In this context, P-type ATPases are interesting therapeutic targets due to their key role in ion homeostasis across the plasma membrane and the mycobacterial survival inside macrophages. In this review, in silico and experimental strategies used for the rational design of new anti-TB drugs are presented; in addition, the chemical space distribution based on the structure and molecular properties of compounds with anti-TB and anti-P-type ATPase activity is discussed. The chemical space distribution compared to public compound libraries demonstrates that natural product libraries are a source of novel chemical scaffolds with potential anti-P-type ATPase activity. Furthermore, compounds that experimentally display anti-P-type ATPase activity belong to a chemical space of molecular properties comparable to that occupied by those approved for oral use, suggesting that these kinds of molecules have a good pharmacokinetic profile (drug-like) for evaluation as potential anti-TB drugs.

Medicinal Chemistry of New Compounds to Treat Tuberculosis

Tuberculosis (TB), a 19th century disease, is still present in the beginning of the Third Millennium. It has been considered pandemic, since around two billion people are infected with M. tuberculosis. Multi-drug resistant TB has been the biggest challenge for chemotherapy. In order to face this severe health problem, many institutions, private and public ones, have been investing in the search for new and better drug candidates. The pipeline of potential anti-TB drugs presents new molecules and formulations that have been submitted to pre-clinical and clinical assays. Medicinal Chemistry has an important role towards the objective of finding new leads through classic and modern processes. This paper reviews some aspects of this search, emphasizing the features of the main compounds under investigation and those that are in preliminary and final clinical trials and includes the contribution of our laboratory (LAPEN) in the area of designing new anti-TB drug candidates.

Identification of irreversible protein splicing inhibitors as potential anti-TB drugs: insight from hybrid non-covalent/covalent docking virtual screening and molecular dynamics simulations

Tuberculosis is responsible for ~3 million deaths annually and is one of the most prevalent infectious diseases known to mankind. Despite ongoing developments in medicine, the emergence of drug resistant Mycobacterium tuberculosis remains of great interest, specifically in developing countries where medical treatment is not readily available. The aim of this study is to identify and explore the binding affinities of novel potential inhibitors that can irreversibly inhibit the intein protein via a covalent bond formation with its active site cysteine. Our search for new leads as potential protein splicing inhibitors is based on Michael acceptor-like structures since they are strong electrophiles which react covalently with the nucleophilic cysteine SH group in the enzyme active site. Structure-based virtual screening using a hybrid non-covalent/covalent docking was performed. Furthermore, molecular dynamic simulations (MD) and extensive post-dynamic analysis were performed in order to ensure the stability of the docked ligand-enzyme complexes and provide insight into the binding affinities and interaction patterns of the screened inhibitors. Interestingly, three novel hits have shown better binding affinity in comparison to experimentally determined compounds with known protein splicing inhibitory activity. MD simulations also revealed that the docked compounds are fairly stable in the protein active site. Per-residue interaction analysis has highlighted the most important active site residues contributing to the inhibitor binding.

Homology modeling and Molecular docking studies of AS1 (Anthranilate synthase component I (TrpE)) model of Mycobacterium tuberculos

The emergence of multi-drug resistant (MDR) strains of Mycobacterium tuberculosis is the main reason why tuberculosis (TB) continues to be a major health problem worldwide. It is urgent to discover novel anti-mycobacterial agents based on new drug targets for the treatment of TB, especially MDR-TB. Tryptophan biosynthetic pathway, which is essential for the survival of M. tuberculosis and meanwhile absent in mammals, provides potential anti-TB drug targets. One of the promising drug targets in this pathway is anthranilate synthase component I (TrpE), whose role is to catalyze the conversion of chorismate to anthranilate using ammonia as amino source. Anthranilate synthase is an interesting target enzyme for antimicrobial activity due to its presence in microorganisms for the synthesis of the essential amino acid tryptophan. In the present study three compounds Cannabigerolic acid, cannabinolic acid and adhumulone from Cannabis sativa have been used for insilio docking studies. Inhibitory studies (invitro) of these compounds against Microorganism have reported earlier. Our approach is to find out the compounds inhibiting the AS1 of MTB by insilico docking and also find out compounds having similar pharmacophore characters from ZINC database so that those compounds can be procured of synthesized in laboratory and used for AS1 inhibitor studies. This study shows that AS can be used as a target enzyme to investigate the mode of action of our compounds in MTB.

Identification of Novel Gyrase B Inhibitors as Potential Anti-TB drugs: Homology Modelling, Hybrid Virtual Screening and Molecular Dynamics Simulations

Using an integrated computational approach involving homology modelling, pharmacophore/structure-based virtual screening, molecular dynamics simulations and per-residue energy contribution, 10 compounds were proposed as potential TB inhibitors. Via validated docking calculations, binding free energy calculations showed that the proposed compounds presented better binding affinity with DNA gyrase B when compared to novobiocin. The compiled in silico approach employed in this study may serve as a useful tool in the process of the design and development of drugs, not only against TB, but also for a wide range of biological systems.

Synthesis, Biological Evaluation, And Molecular Modeling of Chalcone Derivatives As Potent Inhibitors of Mycobacterium tuberculosis Protein Tyrosine Phosphatases (PtpA and PtpB)

Tuberculosis (TB) is a major infectious disease caused by Mycobacterium tuberculosis (Mtb). According to the World Health Organization (WHO), about 1.8 million people die from TB and 10 million new cases are recorded each year. Recently, a new series of naphthylchalcones has been identified as inhibitors of Mtb protein tyrosine phosphatases (PTPs). In this work, 100 chalcones were designed, synthesized, and investigated for their inhibitory properties against MtbPtps. Structure-activity relationships (SAR) were developed, leading to the discovery of new potent inhibitors with IC(50) values in the low-micromolar range. Kinetic studies revealed competitive inhibition and high selectivity toward the Mtb enzymes. Molecular modeling investigations were carried out with the aim of revealing the most relevant structural requirements underlying the binding affinity and selectivity of this series of inhibitors as potential anti-TB drugs.

Antimycobacterial evaluation and preliminary phytochemical investigation of selected medicinal plants traditionally used in Mozambique

Several medicinal plants are traditionally used in Mozambique to treat tuberculosis and related symptoms. It was aimed to assess the in vitro antimycobacterial activity of crude extracts from fifteen medicinal plants and to reveal main classes of compounds which may account for the activity of extracts. The plant materials were sequentially extracted by n-hexane, dichloromethane, ethyl acetate, and 70% ethanol. Decoction of each plant material was also prepared according to traditional use. Broth microdilution method was employed to screen extracts against two mycobacterial species: Mycobacterium smegmatis ATCC 607 and Mycobacterium tuberculosis H37Rv. The extracts with minimum inhibitory concentration(s) (MIC) below 125 μg/mL were considered active and further tested against different mycobacterial species and strains, namely Mycobacterium tuberculosis H37Ra, Mycobacterium bovis BCG ATCC 35734, Mycobacterium smegmatis mc(2) 155, Mycobacterium avium DSM 44156 and DSM 44157. Cytotoxic effect was evaluated against human macrophages from the monocytic THP-1 cells. Main classes of compounds in these active extracts were proposed from their (1)H NMR spectroscopic characterizations. n-Hexane extracts of Maerua edulis and Securidaca longepedunculata, ethyl acetate extract of Tabernaemontana elegans and dichloromethane extract of Zanthoxylum capense were found to possess considerable activity against Mycobacterium bovis BCG and Mycobacterium tuberculosis H37Ra with MIC 15.6-62.5 μg/mL. Tabernaemontana elegans ethyl acetate extract displayed strong activity against Mycobacterium tuberculosis H37Rv (MIC 15.6 μg/mL). Except for Tabernaemontana elegans ethyl acetate extract which presented potent cytotoxic effects in THP-1 cells (IC(50)<4 μg/mL), the other three plant extracts showed moderate to none toxicity. Based on (1)H NMR spectroscopic analysis, major components in both Maerua edulis and Securidaca longepedunculata n-hexane extracts were linear chain unsaturated fatty acids. Zanthoxylum capense dichloromethane extract contained more complex constituents (mostly phenolic compounds). In the most potent extract, Tabernaemontana elegans ethyl acetate extract, the prominent compounds were identified as indole alkaloids. The pronounced antimycobacterial activity of the medicinal plants Maerua edulis, Securidaca longepedunculata, Zanthoxylum capense, and Tabernaemontana elegans suggested that they might provide compounds which could be potential anti-TB drug leads.