Anti-Mycobacterial Peroxides: A New Class of Agents for Development Against Tuberculosis

2020 ◽  
Vol 16 (3) ◽  
pp. 392-402
Author(s):  
Christiaan W. van der Westhuyzen ◽  
Richard K. Haynes ◽  
Jenny-Lee Panayides ◽  
Ian Wiid ◽  
Christopher J. Parkinson
Keyword(s):  
Subsequent Development ◽  
Antitubercular Activity ◽  
Organic Peroxide ◽  
New Drugs ◽  
Skeletal Myoblast ◽  
Artemisinin Derivatives ◽  
Malaria Therapy ◽  
New Class ◽  
Alternative Approach

Background: With few exceptions, existing tuberculosis drugs were developed many years ago and resistance profiles have emerged. This has created a need for new drugs with discrete modes of action. There is evidence that tuberculosis (like other bacteria) is susceptible to oxidative pressure and this has yet to be properly utilised as a therapeutic approach in a manner similar to that which has proven highly successful in malaria therapy. Objective: To develop an alternative approach to the incorporation of bacterial siderophores that results in the creation of antitubercular peroxidic leads for subsequent development as novel agents against tuberculosis. Methods: Eight novel peroxides were prepared and the antitubercular activity (H37Rv) was compared to existing artemisinin derivatives in vitro. The potential for toxicity was evaluated against the L6 rat skeletal myoblast and HeLa cervical cancer lines in vitro. Results: The addition of a pyrimidinyl residue to an artemisinin or, preferably, a tetraoxane peroxidic structure results in antitubercular activity in vitro. The same effect is not observed in the absence of the pyrimidine or with other heteroaromatic substituents. Conclusion: The incorporation of a pyrimidinyl residue adjacent to the peroxidic function in an organic peroxide results in anti-tubercular activity in an otherwise inactive peroxidic compound. This will be a useful approach for creating oxidative drugs to target tuberculosis.

scholarly journals Antineoplastic kinase inhibitors: A new class of potent anti-amoebic compounds

2021 ◽  
Vol 15 (2) ◽  
pp. e0008425
Author(s):  
Conall Sauvey ◽  
Gretchen Ehrenkaufer ◽  
Da Shi ◽  
Anjan Debnath ◽  
Ruben Abagyan
Keyword(s):  
Kinase Inhibitors ◽  
Model Organism ◽  
Protozoan Parasite ◽  
Drug Candidates ◽  
New Class ◽  
Alternative Approach ◽  
The 1960S ◽  
Approved Drugs ◽  
Micromolar Range

Entamoeba histolytica is a protozoan parasite which infects approximately 50 million people worldwide, resulting in an estimated 70,000 deaths every year. Since the 1960s E. histolytica infection has been successfully treated with metronidazole. However, drawbacks to metronidazole therapy exist, including adverse effects, a long treatment course, and the need for an additional drug to prevent cyst-mediated transmission. E. histolytica possesses a kinome with approximately 300–400 members, some of which have been previously studied as potential targets for the development of amoebicidal drug candidates. However, while these efforts have uncovered novel potent inhibitors of E. histolytica kinases, none have resulted in approved drugs. In this study we took the alternative approach of testing a set of twelve previously FDA-approved antineoplastic kinase inhibitors against E. histolytica trophozoites in vitro. This resulted in the identification of dasatinib, bosutinib, and ibrutinib as amoebicidal agents at low-micromolar concentrations. Next, we utilized a recently developed computational tool to identify twelve additional drugs with human protein target profiles similar to the three initial hits. Testing of these additional twelve drugs led to the identification of ponatinib, neratinib, and olmutinib were identified as highly potent, with EC50 values in the sub-micromolar range. All of these six drugs were found to kill E. histolytica trophozoites as rapidly as metronidazole. Furthermore, ibrutinib was found to kill the transmissible cyst stage of the model organism E. invadens. Ibrutinib thus possesses both amoebicidal and cysticidal properties, in contrast to all drugs used in the current therapeutic strategy. These findings together reveal antineoplastic kinase inhibitors as a highly promising class of potent drugs against this widespread and devastating disease.

An efficient synthesis of some new chalcone, acetyl pyrazoline and amino pyrimidine bearing 1,3,5- triazine nucleus as potential antimicrobial and antitubercular agent

2019 ◽  
Author(s):  
Chem Int
Keyword(s):  
Antimicrobial Activity ◽  
Guanidine Hydrochloride ◽  
Antitubercular Activity ◽  
Dilution Method ◽  
Mycobacterium Tuberculosis H37rv ◽  
New Class ◽  
Chemical Structures ◽  
Lowenstein Jensen ◽  
Amino Pyrimidine

In an attempt to find a new class of antimicrobial and antitubercular agent, a new series of chalcone, acetyl pyrazoline and amino pyrimidine bearing 1,3,5- triazine nucleus were synthesized with appropriate chemical reagent. Chalcones (D1-D5) were synthesized by the classical Claisen-Schmidt condensation of substituted ketone (C) with variously substituted aldehydes via conventional method. Now treatment of chalcones with hydrazine hydrate/glacial acetic acid and guanidine hydrochloride/Alkali afforded the corresponding acetyl pyrazoline (E1-E5) and amino pyrimidine (F1-F5) derivatives respectively. The chemical structures of all newly synthesized compounds were established on the basis of their FTIR, 1H NMR, 13C NMR, LC-MS as well as elemental analysis. All the newly design compounds were assayed for their in vitro antimicrobial activity against selected pathogens by the Broth dilution method and in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv using Lowenstein-Jensen MIC method. Most of the compounds showed appreciable antimicrobial activity against the all tested strains. Among the synthesized compounds D1, D2, D3, E1, E3, E4, F3 and F4 exhibited excellent antimicrobial activity and said to be the most proficient members of the series. Compound D5 and F5 exhibited promising antitubercular activity.

Synthesis and In-silico identification of new bioactive 1,3,4-oxadiazole tagged 2,3-dihydroimidazo[1,2-a]pyridine derivatives

2020 ◽  
Vol 16 ◽  
Author(s):  
Bhagwat S. Jadhav ◽  
Vipul P. Purohit ◽  
Ramesh S. Yamgar ◽  
Rajesh S. Kenny ◽  
Suraj N. Mali ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Anticancer Activity ◽  
In Silico ◽  
Antitubercular Activity ◽  
Docking Studies ◽  
Pyridine Derivatives ◽  
Molecular Docking Studies ◽  
New Class ◽  
In Silico Molecular Docking

Background: Tuberculosis (TB) continues to be the most threatening cause of death in recent years. There is urgent need of search more potent, less toxic antitubercular agents. Methods: A set of five new 1,3,4-oxadiazolyl-imidazo-1,2-pyridine derivatives (4a-4e) was synthesized and screened invitro for their antibacterial activity against Mycobacterium tuberculosis (H37 RV strain) ATCC No-27294. Results: Compound 4b displayed potent antitubercular activity at MIC 6.25 µg/mL. In-silico molecular docking studies were performed for evaluation of the binding patterns of compounds 4a-4e in the binding site of proteins like, Pantothenate synthatase and enoyl acyl reductase inhibitor. The outcomes of the in- vitro antitubercular studies were in well agreement with the molecular docking studies. These newly synthesized compounds were found to have good ADMET profile. We also explored possible anticancer activity using in-silico methods. Conclusion: These results shows that readily synthesized 1,3,4-oxadiazolyl-imidazo-1,2-pyridine derivatives (4a-4e) are attracting new class of potent anti-TB targets as well as possible anticancer activity that worth additional opportunities for improvements.

Synthesis, biology, computational studies and in vitro controlled release of new isoniazid-based adamantane derivatives

2019 ◽  
Vol 11 (21) ◽  
pp. 2779-2802 ◽  
Author(s):  
Andria Papageorgiou ◽  
Angeliki-Sofia Foscolos ◽  
Ioannis P Papanastasiou ◽  
Marilena Vlachou ◽  
Angeliki Siamidi ◽  
...  
Keyword(s):  
Antitubercular Activity ◽  
New Drugs ◽  
In Vivo Studies ◽  
Adamantane Derivatives ◽  
Dissolution Profile ◽  
Pharmacological Test ◽  
Dynamics Simulations ◽  
Drug Resistant Strains

Aim: There is a necessity for new drugs to be more efficient than today's standard due to the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb) Results/methodology: 12 new isoniazid-based adamantane derivatives were synthesized and tested for their antitubercular activity. The pharmacological test results and the aqueous dissolution profile of representative examples of the new molecules are in agreement with the computational results obtained from docking poses and molecular dynamics simulations on the tested compounds. Conclusion: Among their congeners, the adamantane isonicotinoyl hydrazones Ia and Ih exhibit the best antitubercular activity (MIC = 0.04 μg/ml) and the lowest cytotoxicity (selectivity index ≥2500). These results are useful for in future in vivo studies.

scholarly journals Characterization of the TCL-1 transgenic mouse as a preclinical drug development tool for human chronic lymphocytic leukemia

Blood ◽  
2006 ◽  
Vol 108 (4) ◽  
pp. 1334-1338 ◽  
Author(s):  
Amy J. Johnson ◽  
David M. Lucas ◽  
Natarajan Muthusamy ◽  
Lisa L. Smith ◽  
Ryan B. Edwards ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Drug Development ◽  
Transgenic Mouse ◽  
Subsequent Development ◽  
Lymphocytic Leukemia ◽  
New Drugs ◽  
Clinical Activity ◽  
Suitable Animal Model

Abstract Drug development in human chronic lymphocytic leukemia (CLL) has been limited by lack of a suitable animal model to adequately assess pharmacologic properties relevant to clinical application. A recently described TCL-1 transgenic mouse develops a chronic B-cell CD5+ leukemia that might be useful for such studies. Following confirmation of the natural history of this leukemia in the transgenic mice, we demonstrated that the transformed murine lymphocytes express relevant therapeutic targets (Bcl-2, Mcl-1, AKT, PDK1, and DNMT1), wild-type p53 status, and in vitro sensitivity to therapeutic agents relevant to the treatment of human CLL. We then demonstrated the in vivo clinical activity of low-dose fludarabine in transgenic TCL-1 mice with active leukemia. These studies demonstrated both early reduction in blood-lymphocyte count and spleen size and prolongation of survival (P = .046) compared with control mice. Similar to human CLL, an emergence of resistance was noted with fludarabine treatment in vivo. Overall, these studies suggest that the TCL-1 transgenic leukemia mouse model has similar clinical and therapeutic response properties to human CLL and may therefore serve as a useful in vivo tool to screen new drugs for subsequent development in CLL.

scholarly journals Treatment of Murine Cerebral Malaria by Artemisone in Combination with Conventional Antimalarial Drugs: Antiplasmodial Effects and Immune Responses

2014 ◽  
Vol 58 (8) ◽  
pp. 4745-4754 ◽  
Author(s):  
W. Armand Guiguemde ◽  
Nicholas H. Hunt ◽  
Jintao Guo ◽  
Annael Marciano ◽  
Richard K. Haynes ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Antimalarial Activity ◽  
Interleukin 10 ◽  
Antimalarial Drugs ◽  
New Drugs ◽  
Artemisinin Derivative ◽  
Content Type ◽  
Artemisinin Derivatives ◽  
Dual Action

ABSTRACTThe decreasing effectiveness of antimalarial therapy due to drug resistance necessitates constant efforts to develop new drugs. Artemisinin derivatives are the most recent drugs that have been introduced and are considered the first line of treatment, but there are already indications ofPlasmodium falciparumresistance to artemisinins. Consequently, drug combinations are recommended for prevention of the induction of resistance. The research here demonstrates the effects of novel combinations of the new artemisinin derivative, artemisone, a recently described 10-alkylamino artemisinin derivative with improved antimalarial activity and reduced neurotoxicity. We here investigate its ability to killP. falciparumin a high-throughputin vitroassay and to protect mice against lethal cerebral malaria caused byPlasmodium bergheiANKA when used alone or in combination with established antimalarial drugs. Artemisone effects againstP. falciparumin vitrowere synergistic with halofantrine and mefloquine, and additive with 25 other drugs, including chloroquine and doxycycline. The concentrations of artemisone combinations that were toxic against THP-1 cellsin vitrowere much higher than their effective antimalarial concentration. Artemisone, mefloquine, chloroquine, or piperaquine given individually mostly protected mice against cerebral malaria caused byP. bergheiANKA but did not prevent parasite recrudescence. Combinations of artemisone with any of the other three drugs did completely cure most mice of malaria. The combination of artemisone and chloroquine decreased the ratio of proinflammatory (gamma interferon, tumor necrosis factor) to anti-inflammatory (interleukin 10 [IL-10], IL-4) cytokines in the plasma ofP. berghei-infected mice. Thus, artemisone in combinations with other antimalarial drugs might have a dual action, both killing parasites and limiting the potentially deleterious host inflammatory response.

scholarly journals Bengamides display potent activity against drug-resistant Mycobacterium tuberculosis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Diana H. Quan ◽  
Gayathri Nagalingam ◽  
Ian Luck ◽  
Nicholas Proschogo ◽  
Vijaykumar Pillalamarri ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
New Drugs ◽  
Bioactive Molecules ◽  
Aminopeptidase Activity ◽  
Drug Resistant ◽  
Lead Compounds ◽  
New Class ◽  
Tb Treatment ◽  
Bioassay Guided Fractionation

Abstract Mycobacterium tuberculosis infects over 10 million people annually and kills more people each year than any other human pathogen. The current tuberculosis (TB) vaccine is only partially effective in preventing infection, while current TB treatment is problematic in terms of length, complexity and patient compliance. There is an urgent need for new drugs to combat the burden of TB disease and the natural environment has re-emerged as a rich source of bioactive molecules for development of lead compounds. In this study, one species of marine sponge from the Tedania genus was found to yield samples with exceptionally potent activity against M. tuberculosis. Bioassay-guided fractionation identified bengamide B as the active component, which displayed activity in the nanomolar range against both drug-sensitive and drug-resistant M. tuberculosis. The active compound inhibited in vitro activity of M. tuberculosis MetAP1c protein, suggesting the potent inhibitory action may be due to interference with methionine aminopeptidase activity. Tedania-derived bengamide B was non-toxic against human cell lines, synergised with rifampicin for in vitro inhibition of bacterial growth and reduced intracellular replication of M. tuberculosis. Thus, bengamides isolated from Tedania sp. show significant potential as a new class of compounds for the treatment of drug-resistant M. tuberculosis.

5. Making new medicines

2016 ◽  
Author(s):  
Les Iversen
Keyword(s):  
New Drugs ◽  
Pharmaceutical Companies ◽  
New Class ◽  
Drug Prices ◽  
Animal Trials ◽  
Three Phase ◽  
The Government ◽  
Receptor Targets ◽  
Expensive Process

‘Making new medicines’ outlines the process of developing and marketing new drugs. Advanced techniques provide scientists with many potential receptor targets. Compounds which may affect the target are tested in vitro. If they appear to work further tests are carried out, increasing in complexity from cells to whole organisms. Animal trials help forecast toxicity and determine dosages. Finally, three-phase clinical trials occur in humans. Pharmaceutical companies then submit their data to the government for approval, before the drug can be sold. The lengthy and expensive process often results in high drug prices. A relatively new class of medicines—monoclonal antibodies—is having a major impact in treating hitherto untreatable conditions.

scholarly journals Synthesis, structural characterization and antimycobacterial evaluation of several halogenated non-nitro benzothiazinones

2021 ◽  
Author(s):  
Balungile Madikizela ◽  
Tamira Eckhardt ◽  
Richard Goddard ◽  
Adrian Richter ◽  
Anika Lins ◽  
...  
Keyword(s):  
Structural Characterization ◽  
Antitubercular Activity ◽  
In Vitro Testing ◽  
Antitubercular Agents ◽  
Cell Wall Synthesis ◽  
X Ray ◽  
X Ray Crystallography ◽  
New Class ◽  
Mycobacterium Aurum

Abstract8-Nitro-1,3-benzothiazin-4-ones (BTZs), with BTZ043 and PBTZ169 as the most advanced compounds, represent a new class of potent antitubercular agents, which irreversibly inhibit decaprenylphosphoryl-β-d-ribose-2′-epimerase (DprE1), an enzyme crucial for cell wall synthesis in the pathogen Mycobacterium tuberculosis. Synthesis, structural characterization and in vitro testing against Mycobacterium aurum DSM 43999 and M. tuberculosis H37Rv of halogenated 2-(4-ethoxycarbonylpiperazin-1-yl)-1,3-benzothiazin-4-ones lacking a nitro group are reported. X-ray crystallography reveals that the structure of the BTZ scaffold can significantly deviate from planarity. In contrast to recent reports, the results of the present study indicate that further investigation of halogenated non-nitro BTZs for antitubercular activity is less than a promising approach.

scholarly journals The Prospect of Repurposing Immunomodulatory Drugs for Adjunctive Chemotherapy against Tuberculosis: A Critical Review

Antibiotics ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 91
Author(s):  
Chiyun Lee ◽  
Sanjib Bhakta
Keyword(s):  
Antitubercular Activity ◽  
New Drugs ◽  
Immunomodulatory Drugs ◽  
Standard Regimen ◽  
Treatment Development ◽  
Treatment Regimens ◽  
Promising Strategy ◽  
Conventional Drug

Tuberculosis (TB) remains a global health emergency, with an estimated 2 billion people infected across the world, and 1.4 million people dying to this disease every year. Many aspects of the causative agent, Mycobacterium tuberculosis, make this disease difficult for healthcare and laboratory researchers to fight against, such as unique pathophysiology, latent infection and long and complex treatment regimens, thus causing patient non-compliance with the treatment. Development of new drugs is critical for tackling these problems. Repurposing drugs is a promising strategy for generating an effective drug treatment whilst circumventing many of the challenges of conventional drug development. In this regard, the incorporation of immunomodulatory drugs into the standard regimen to potentiate frontline drugs is found to be highly appealing. Drugs of diverse chemical classes and drug categories are increasingly being evidenced to possess antitubercular activity, both in vitro and in vivo. This article explores and discusses the molecular entities that have shown promise in being repurposed for use in anti-TB adjunctive therapy and aims to provide the most up-to-date picture of their progress.

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