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European Journal of Medicinal Chemistry Aug 2022Tuberculosis, a disease of poverty is a communicable infection with a reasonably high mortality rate worldwide. 10 Million new cases of TB were reported with approx 1.4... (Review)
Review
Tuberculosis, a disease of poverty is a communicable infection with a reasonably high mortality rate worldwide. 10 Million new cases of TB were reported with approx 1.4 million deaths in the year 2019. Due to the growing number of drug-sensitive and drug-resistant tuberculosis cases, there is a vital need to develop new and effective candidates useful to combat this deadly disease. Despite tremendous efforts to identify a mechanism-based novel antitubercular agent, only a few have entered into clinical trials in the last six decades. In recent years, triazoles have been well explored as the most valuable scaffolds in drug discovery and development. Triazole framework possesses favorable properties like hydrogen bonding, moderate dipole moment, enhanced water solubility, and also the ability to bind effectively with biomolecular targets of M. tuberculosis and therefore this scaffold displayed excellent potency against TB. This review is an endeavor to summarize an up-to-date innovation of triazole-appended hybrids during the last 10 years having potential in vitro and in vivo antitubercular activity with structure activity relationship analysis. This review may help medicinal chemists to explore the triazole scaffolds for the rational design of potent drug candidates having better efficacy, improved selectivity and minimal toxicity so that these hybrid NCEs can effectively be explored as potential lead to fight against M. tuberculosis.
Topics: Antitubercular Agents; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Structure-Activity Relationship; Triazoles; Tuberculosis
PubMed: 35597009
DOI: 10.1016/j.ejmech.2022.114454 -
International Journal of Antimicrobial... Jun 2016Resistance and tolerance to antituberculosis (anti-TB) drugs, especially the first-line drugs, has become a serious problem in anti-TB therapy. Efflux of antimicrobial... (Review)
Review
Resistance and tolerance to antituberculosis (anti-TB) drugs, especially the first-line drugs, has become a serious problem in anti-TB therapy. Efflux of antimicrobial agents via bacterial efflux pumps is one of the main reasons for drug resistance. Efflux pump inhibitors (EPIs) bind to efflux pumps to inhibit drug efflux and thus enhance the drug effect and reduce drug resistance. Studies on EPIs targeting the efflux pumps of Mycobacterium tuberculosis (Mtb) help to understand Mtb resistance and to identify the potential drug target and are of significance in guiding the development of new anti-TB drugs and optimal combinations. Currently, there are many potential EPIs under study, but none of them has been used clinically for anti-TB therapy. In this article, we will provide an overview on the current development of EPIs targeting the efflux pumps of Mtb and discuss their potential clinical applications.
Topics: Antitubercular Agents; Biological Transport, Active; Drug Discovery; Mycobacterium tuberculosis
PubMed: 27211826
DOI: 10.1016/j.ijantimicag.2016.04.007 -
Current Protein & Peptide Science 2022Natural cyclic peptide scaffolds are indispensable in medicinal chemistry, chemical biology, and drug discovery platforms due to their chemical diversity, structural... (Review)
Review
Natural cyclic peptide scaffolds are indispensable in medicinal chemistry, chemical biology, and drug discovery platforms due to their chemical diversity, structural integrity, proteolytic stability and biocompatibility. Historically, their isolation and profound understanding of target engagement have been identified as lead pharmacophore discovery. Natural cyclic peptides are the largest class of pharmacologically active scaffold, in which most show activity against drug-resistant Mycobacterium tuberculosis (Mtb). Nevertheless, eight recently discovered cyclic peptide scaffolds exhibit promising antitubercular activity among numerous naturally occurring antitubercular peptides, and they are amenable scaffolds to drug development. We examined their biological origin, scaffolds, isolations, chemical synthesis, and reasons for biological actions against Mtb. Understanding these peptide scaffold details will further allow synthetic and medicinal chemists to develop novel peptide therapeutics against tuberculosis-infected deadly diseases. This review emphasizes these cyclic peptides' in vitro and in vivo activity profiles, including their structural and chemical features.
Topics: Humans; Peptides, Cyclic; Antitubercular Agents; Tuberculosis; Peptides; Drug Discovery; Mycobacterium tuberculosis
PubMed: 36200246
DOI: 10.2174/1389203723666220930111259 -
Current Opinion in Microbiology Oct 2022Tuberculosis (TB) persists as a major global health issue and a leading cause of death by a single infectious agent. The global burden of TB is further exacerbated by... (Review)
Review
Tuberculosis (TB) persists as a major global health issue and a leading cause of death by a single infectious agent. The global burden of TB is further exacerbated by the continuing emergence and dissemination of strains of Mycobacterium tuberculosis resistant to multiple antibiotics. The need for novel drugs that can be used to shorten the course for current TB drug regimens as well as combat the persistent threat of antibiotic resistance has never been greater. There have been significant advances in the discovery of de novo TB treatments, with the first TB-specific drugs in 45 years approved for use. However, there are still issues that restrict the pipeline of new antitubercular chemotherapies. The rate of failure of TB drug candidates in clinical trials remains high, while the validation of new TB drug targets and subsequent identification of novel inhibitors remains modest.
Topics: Antitubercular Agents; Drug Delivery Systems; Humans; Mycobacterium tuberculosis; Tuberculosis
PubMed: 35970040
DOI: 10.1016/j.mib.2022.102191 -
Progress in Biophysics and Molecular... May 2020Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), kills more people than any other bacterium. TB control is threatened by the continued spread... (Review)
Review
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), kills more people than any other bacterium. TB control is threatened by the continued spread of drug resistance; multi-drug and extensively drug resistant Mtb require longer, more costly, treatment with multiple drugs causing worse side effects and have a lower likelihood of treatment success. The urgent need for better treatment options for drug resistant Mtb has led the World Health Organization to prioritize development of not only new individual antitubercular agents, but also new drug regimens. This introductory chapter of the special issue Novel insights into TB research and drug discovery within Progress in Biophysics and Molecular Biology, gives a short overview about the general problems of TB and the treatment of this disease today, and introduces the review topics within this issue.
Topics: Animals; Antitubercular Agents; Disease Models, Animal; Drug Discovery; Drug Resistance; Humans; Mycobacterium tuberculosis; Signal Transduction; Tuberculosis; World Health Organization
PubMed: 32087187
DOI: 10.1016/j.pbiomolbio.2020.02.003 -
Current Medicinal Chemistry 2019Infections with Mycobacterium tuberculosis, the causative agent of tuberculosis, are difficult to treat using currently available chemotherapeutics. Clinicians agree on... (Review)
Review
Infections with Mycobacterium tuberculosis, the causative agent of tuberculosis, are difficult to treat using currently available chemotherapeutics. Clinicians agree on the urgent need for novel drugs to treat tuberculosis. In this mini review, we summarize data that prompts the consideration of DNA repair-associated proteins as targets for the development of new antitubercular compounds. We discuss data, including gene expression data, that highlight the importance of DNA repair genes during the pathogenic cycle as well as after exposure to antimicrobials currently in use. Specifically, we report experiments on determining the essentiality of DNA repair-related genes. We report the availability of protein crystal structures and summarize discovered protein inhibitors. Further, we describe phenotypes of available gene mutants of M. tuberculosis and model organisms Mycobacterium bovis and Mycobacterium smegmatis. We summarize experiments regarding the role of DNA repair-related proteins in pathogenesis and virulence performed both in vitro and in vivo during the infection of macrophages and animals. We detail the role of DNA repair genes in acquiring mutations, which influence the rate of drug resistance acquisition.
Topics: Animals; Antitubercular Agents; Bacterial Proteins; DNA Repair; DNA Repair Enzymes; DNA, Bacterial; Drug Development; Gene Expression Regulation, Bacterial; Humans; Molecular Targeted Therapy; Mutation Rate; Mycobacterium; Tuberculosis
PubMed: 29376490
DOI: 10.2174/0929867325666180129093546 -
Future Medicinal Chemistry Dec 2021Tuberculosis is a deadly communicable disease caused by the bacillus (MTB), and pulmonary tuberculosis accounts for over 80% of the total cases. The 1,2,4-triazole is... (Review)
Review
Tuberculosis is a deadly communicable disease caused by the bacillus (MTB), and pulmonary tuberculosis accounts for over 80% of the total cases. The 1,2,4-triazole is a privileged structure in the discovery of new drugs, and its derivatives act on various targets in MTB. In particular, 1,2,4-triazole hybrids can not only exert dual or multiple antitubercular mechanisms of action but also have the potential to enhance efficacy and reduce side effects. The present work aims to summarize the current status of 1,2,4-triazole hybrids as potential antitubercular agents, covering articles published between 2010 and 2020, to aid the further rational design of novel potential drug candidates endowed with higher efficacy, better compliance and fewer side effects.
Topics: Antitubercular Agents; Humans; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Structure-Activity Relationship; Triazoles
PubMed: 34698509
DOI: 10.4155/fmc-2020-0295 -
Biomolecules Aug 2021Curcumin is the principal curcuminoid obtained from the plant and has been extensively studied for its biological and chemical properties. Curcumin displays a vast... (Review)
Review
Curcumin is the principal curcuminoid obtained from the plant and has been extensively studied for its biological and chemical properties. Curcumin displays a vast range of pharmacological properties, including antimicrobial, anti-inflammatory, antioxidant, and antitumor activity. Specifically, curcumin has been linked to the improvement of the outcome of tuberculosis. There are many reviews on the pharmacological effects of curcumin; however, reviews of the antitubercular activity are comparatively scarcer. In this review, we attempt to discuss the different aspects of the research on the antitubercular activity of curcumin. These include antimycobacterial activity, modulation of the host immune response, and enhancement of BCG vaccine efficacy. Recent advances in the antimycobacterial activity of curcumin synthetic derivatives, the role of computer aided drug design in identifying curcumin targets, the hepatoprotective role of curcumin, and the dosage and toxicology of curcumin will be discussed. While growing evidence supports the use of curcumin and its derivatives for tuberculosis therapy, further preclinical and clinical investigations are of pivotal importance before recommending the use of curcumin formulations in public health.
Topics: Animals; Antitubercular Agents; Curcumin; Dose-Response Relationship, Drug; Drug Design; Humans; Liver; Mycobacterium tuberculosis
PubMed: 34572491
DOI: 10.3390/biom11091278 -
Organic & Biomolecular Chemistry Jun 2019Antituberculosis drugs have captured the attention of the scientific community due to the emergence of drug resistance. Hence, the development of new analogs and new... (Review)
Review
Antituberculosis drugs have captured the attention of the scientific community due to the emergence of drug resistance. Hence, the development of new analogs and new drugs which can treat drug-resistant tuberculosis is required. In this report, we reviewed the strategies towards the synthesis of antituberculosis drugs. These strategies include semisynthetic approaches, resolution based strategies, microbial transformations, solid phase synthesis, and asymmetric synthesis. As stereochemistry is an important hallmark of many drugs, the strategies based on asymmetric synthesis are described in detail. The emphasis on semisynthetic approaches is given for aminoglycoside antibiotics.
Topics: Antitubercular Agents; Humans; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 31111850
DOI: 10.1039/c9ob00817a -
Bioorganic & Medicinal Chemistry Mar 2023Among the various bacterial infections, tuberculosis continues to hold center stage. Its causative agent, Mycobacterium tuberculosis, possesses robust defense mechanisms... (Review)
Review
Among the various bacterial infections, tuberculosis continues to hold center stage. Its causative agent, Mycobacterium tuberculosis, possesses robust defense mechanisms against most front-line antibiotic drugs and host responses due to their complex cell membranes with unique lipid molecules. It is now well-established that bacteria change their membrane composition to optimize their environment to survive and elude drug action. Thus targeting membrane or membrane components is a promising avenue for exploiting the chemical space focussed on developing novel membrane-centric anti-bacterial small molecules. These approaches are more effective, non-toxic, and can attenuate resistance phenotype. We present the relevance of targeting the mycobacterial membrane as a practical therapeutic approach. The review highlights the direct and indirect targeting of membrane structure and function. Direct membrane targeting agents cause perturbation in the membrane potential and can cause leakage of the cytoplasmic contents. In contrast, indirect membrane targeting agents disrupt the function of membrane-associated proteins involved in cell wall biosynthesis or energy production. We discuss the chronological chemical improvements in various scaffolds targeting specific membrane-associated protein targets, their clinical evaluation, and up-to-date account of their ''mechanisms of action, potency, selectivity'' and limitations. The sources of anti-TB drugs/inhibitors discussed in this work have emerged from target-based identification, cell-based phenotypic screening, drug repurposing, and natural products. We believe this review will inspire the exploration of uncharted chemical space for informing the development of new scaffolds that can inhibit novel mycobacterial membrane targets.
Topics: Humans; Antitubercular Agents; Membrane Proteins; Mycobacterium tuberculosis; Tuberculosis; Bacterial Proteins
PubMed: 36804747
DOI: 10.1016/j.bmc.2023.117212