scholarly journals Identification of Novel Chemical Scaffolds that Inhibit the Growth of Mycobacterium tuberculosis in Macrophages

2022 ◽  
Vol 12 ◽  
Author(s):  
Sara Ahmed ◽  
Alyssa Manning ◽  
Lindsay Flint ◽  
Divya Awasthi ◽  
Yulia Ovechkina ◽  
...  

Mycobacterium tuberculosis is an important global pathogen for which new drugs are urgently required. The ability of the organism to survive and multiply within macrophages may contribute to the lengthy treatment regimen with multiple drugs that are required to cure the infection. We screened the MyriaScreen II diversity library of 10,000 compounds to identify novel inhibitors of M. tuberculosis growth within macrophage-like cells using high content analysis. Hits were selected which inhibited the intramacrophage growth of M. tuberculosis without significant cytotoxicity to infected macrophages. We selected and prioritized compound series based on their biological and physicochemical properties and the novelty of the chemotypes. We identified five chemical classes of interest and conducted limited catalog structure-activity relationship studies to determine their tractability. We tested activity against intracellular and extracellular M. tuberculosis, as well as cytoxicity against murine RAW264.7 and human HepG2 cells. Benzene amide ethers, thiophene carboxamides and thienopyridines were only active against intracellular bacteria, whereas the phenylthiourea series was also active against extracellular bacteria. One member of a phenyl pyrazole series was moderately active against extracellular bacteria. We identified the benzene amide ethers as an interesting series for further work. These new compound classes serve as starting points for the development of novel drugs to target intracellular M. tuberculosis.

2021 ◽  
Author(s):  
Sara Ahmed ◽  
Alyssa J Manning ◽  
Lindsay Flint ◽  
Divya Awasthi ◽  
Tanya Parish

Mycobacterium tuberculosis is an important global pathogen for which new drugs are urgently required. The ability of the organism to survive and multiply within macrophages may contribute to the lengthy treatment regimen with multiple drugs that are required to cure the infection. We screened the MyriaScreen II diversity library of 10,000 compounds to identify novel inhibitors of M. tuberculosis growth within macrophage-like cells using high content analysis. Hits were selected which inhibited the intramacrophage growth of M. tuberculosis without significant cytotoxicity to infected macrophages. We selected and prioritized compound series based on their biological and physicochemical properties and the novelty of the chemotypes. We identified five chemical classes of interest and conducted limited catalog structure-activity relationship studies to determine their tractability. We tested activity against intracellular and extracellular M.tuberculosis, as well as cytoxicity against murine RAW264.7 and human HepG2 cells. Benzene amide ethers, thiophene carboxamides and thienopyridines were only active against intracellular bacteria, whereas the phenylthiourea series was also active against extracellular bacteria. One member of a phenyl pyrazole series was moderately active against extracellular bacteria. We identified the benzene amide ethers as an interesting series for further work. These new compound classes serve as starting points for the development of novel drugs to target intracellular M. tuberculosis.


2021 ◽  
pp. 247255522110024
Author(s):  
Yunhong Nong ◽  
Yanyan Hou ◽  
Yuting Pu ◽  
Si Li ◽  
Yan Lan

Throughout recent decades, histone deacetylase (HDAC) inhibitors have shown encouraging potential in cancer treatment, and several pan-HDAC inhibitors have been approved for treating malignant cancers. Numerous adverse effects of pan-HDAC inhibitors have been reported, however, during preclinical and clinical evaluations. To avoid undesirable responses, an increasing number of investigations are focusing on the development of isotype-selective HDAC inhibitors. In this study, we present an effective and quantitative cellular assay using high-content analysis (HCA) to determine compounds’ inhibition of the activity of HDAC6 and Class I HDAC isoforms, by detecting the acetylation of their corresponding substrates (i.e., α-tubulin and histone H3). Several conditions that are critical for HCA assays, such as cell seeding number, fixation and permeabilization reagent, and antibody dilution, have been fully validated in this study. We used selective HDAC6 inhibitors and inhibitors targeting different HDAC isoforms to optimize and validate the capability of the HCA assay. The results indicated that the HCA assay is a robust assay for quantifying compounds’ selectivity of HDAC6 and Class I HDAC isoforms in cells. Moreover, we screened a panel of compounds for HDAC6 selectivity using this HCA assay, which provided valuable information for the structure–activity relationship (SAR). In summary, our results suggest that the HCA assay is a powerful tool for screening selective HDAC6 inhibitors.


2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Saqib Kidwai ◽  
Chan-Yong Park ◽  
Shradha Mawatwal ◽  
Prabhakar Tiwari ◽  
Myung Geun Jung ◽  
...  

ABSTRACT New chemotherapeutic agents with novel mechanisms of action are urgently required to combat the challenge imposed by the emergence of drug-resistant mycobacteria. In this study, a phenotypic whole-cell screen identified 5-nitro-1,10-phenanthroline (5NP) as a lead compound. 5NP-resistant isolates harbored mutations that were mapped to fbiB and were also resistant to the bicyclic nitroimidazole PA-824. Mechanistic studies confirmed that 5NP is activated in an F420-dependent manner, resulting in the formation of 1,10-phenanthroline and 1,10-phenanthrolin-5-amine as major metabolites in bacteria. Interestingly, 5NP also killed naturally resistant intracellular bacteria by inducing autophagy in macrophages. Structure-activity relationship studies revealed the essentiality of the nitro group for in vitro activity, and an analog, 3-methyl-6-nitro-1,10-phenanthroline, that had improved in vitro activity and in vivo efficacy in mice compared with that of 5NP was designed. These findings demonstrate that, in addition to a direct mechanism of action against Mycobacterium tuberculosis, 5NP also modulates the host machinery to kill intracellular pathogens.


Author(s):  
D Samba Reddy

This article provides a brief overview of novel drugs approved by the U.S. FDA in 2016.  It also focuses on the emerging boom in the development of neurodrugs for central nervous system (CNS) disorders. These new drugs are innovative products that often help advance clinical care worldwide, and in 2016, twenty-two such drugs were approved by the FDA. The list includes the first new drug for disorders such as spinal muscular atrophy, Duchenne muscular dystrophy or hallucinations and delusions of Parkinson’s disease, among several others. Notably, nine of twenty-two (40%) were novel CNS drugs, indicating the industry shifting to neurodrugs. Neurodrugs are the top selling pharmaceuticals worldwide, especially in America and Europe. Therapeutic neurodrugs have proven their significance many times in the past few decades, and the CNS drug portfolio represents some of the most valuable agents in the current pipeline. Many neuroproducts are vital or essential medicines in the current therapeutic armamentarium, including dozens of “blockbuster drugs” (drugs with $1 billion sales potential).  These drugs include antidepressants, antimigraine medications, and anti-epilepsy medications. The rise in neurodrugs’ sales is predominantly due to increased diagnoses of CNS conditions. The boom for neuromedicines is evident from the recent rise in investment, production, and introduction of new CNS drugs.  There are many promising neurodrugs still in the pipeline, which are developed based on the validated “mechanism-based” strategy. Overall, disease-modifying neurodrugs that can prevent or cure serious diseases, such as multiple sclerosis, epilepsy, and Alzheimer’s disease, are in high demand. 


2018 ◽  
Vol 25 (30) ◽  
pp. 3560-3576 ◽  
Author(s):  
Massimo Tosolini ◽  
Paolo Pengo ◽  
Paolo Tecilla

Natural and synthetic anionophores promote the trans-membrane transport of anions such as chloride and bicarbonate. This process may alter cellular homeostasis with possible effects on internal ions concentration and pH levels triggering several and diverse biological effects. In this article, an overview of the recent results on the study of aniontransporters, mainly acting with a carrier-type mechanism, is given with emphasis on the structure/activity relationship and on their biological activity as antibiotic and anticancer agents and in the development of new drugs for treating conditions derived from dysregulation of natural anion channels.


2020 ◽  
Vol 24 (8) ◽  
pp. 817-854
Author(s):  
Anil Kumar ◽  
Nishtha Saxena ◽  
Arti Mehrotra ◽  
Nivedita Srivastava

Quinolone derivatives have attracted considerable attention due to their medicinal properties. This review covers many synthetic routes of quinolones preparation with their antibacterial properties. Detailed study with structure-activity relationship among quinolone derivatives will be helpful in designing new drugs in this field.


Author(s):  
Md Abul Barkat ◽  
Anjali Goyal ◽  
Harshita Abul Barkat ◽  
Mohammad Salauddin ◽  
Faheem Hyder Pottoo ◽  
...  

Abstract:: Herbal medicines pays an important in treating the vaious diseases mainly due to the their potentially high therapeutic values and also due to the better acceptance of vaioruspatient under different health complications. The herbal medicine practice involves use of part of plant, entire plant or the selectctive isolated phytomedicineand the use and practices based on these has its pros and cons and has been greatly affected during the dawn. The search of new drugs during scientific era revives the interest in discovery of herbal drugs from different natural resources during 20th century. The present modern healthcare system invovlves utilization drugs and 50% of them are of ofnaural origin. Herbal drug disocovery found to be highly costly affair with low success rate and it hinders the further progress in utilizting the phytomedicine in treating the various deseases. But in recent years there is an increase in the search interest of herbal drugs mainly by the pharmaceutical industry and those invoves in the search of novel drugs from the herbs. Discovery of such new novel phytomedicines has to overcomes various challenges in indentification of active extracts and their toxicity, advereffects, herb drug interaction and importantly their regulatory requirments. The present review mainly focused on the history of herbal medicine, current clinical perspective, pharmaceutical, and regulatory challenges as well as its clinical presentation. Moreover, problems encountered in drug discovery from herbal resources and its possible solutions are delineated.


Author(s):  
Deepa Parwani ◽  
Sushanta Bhattacharya ◽  
Akash Rathore ◽  
Chaitali Mallick ◽  
Vivek Asati ◽  
...  

: Tuberculosis is a disease caused by Mycobacterium tuberculosis (Mtb), affecting millions of people worldwide. The emergence of drug resistance is a major problem in the successful treatment of tuberculosis. Due to the commencement of MDR-TB (multi-drug resistance) and XDR-TB (extensively drug resistance), there is a crucial need for the development of novel anti-tubercular agents with improved characteristics such as low toxicity, enhanced inhibitory activity and short duration of treatment. In this direction, various heterocyclic compounds have been synthesized and screened against Mycobacterium tuberculosis. Among them, benzimidazole and imidazole containing derivatives found to have potential anti-tubercular activity. The present review focuses on various imidazole and benzimidazole derivatives (from 2015-2019) with their structure activity relationships in the treatment of tuberculosis.


1994 ◽  
Vol 59 (1) ◽  
pp. 234-238 ◽  
Author(s):  
Karel Waisser ◽  
Jiří Kuneš ◽  
Alexandr Hrabálek ◽  
Želmíra Odlerová

Oxidation of 1-aryltetrazole-5-thiols afforded bis(1-aryltetrazol-5-yl) disulfides. The compounds were tested for antimycobacterial activity against Mycobacterium tuberculosis, M. kansasii, M. avium and M. fortuitum. In the case of M. tuberculosis, the logarithm of minimum inhibitory concentration showed a parabolic dependence on hydrophobic substituent constants. Although the compounds exhibited low to medium activity, the most active derivative, bis(4-chlorophenyltetrazol-5-yl) disulfide (III) was more effective against atypical strains than are the commercial tuberculostatics used as standards.


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