Abstract
In this review, we intend to provide a general view of the evolution of experimental studies in the area of chemotherapy for Chagas disease. We can follow the process of drug development through three phases. The first phase began almost at the same time as the discovery made by Carlos Chagas and proceeds to 1970, during which time an extensive list of compounds was subjected to preclinical and clinical trials. The second phase began with the introduction of nifurtimox and benznidazole into the clinical setting, followed with the search for alternative drugs. In this phase, a dichotomy existed between rational and empirical approaches in preclinical studies. The third phase began with the unravelling of the T. cruzi genome. The development of transgenic parasites has allowed the development of solid HTS protocols, and the establishment of bioluminescent T. cruzi has allowed in vivo drug evaluations using a reduced number of animals. Among the wide variety of compounds subjected to preclinical studies, we have discovered azolic and non-azolic inhibitors of sterol C14α-demethylase (CYP51) and nitro compounds. Two compounds evaluated during the second phase, namely, MK-436 and allopurinol, could be revisited. Clinical studies of posaconazole and E1224 yielded disappointing results, and it is critical to understand the reason for their failure as a monotherapy. Currently, the combination and repositioning of drugs with different mechanisms of action are complementary approaches. The use of drug combinations, particularly those of nitro compounds with CYP51 inhibitors, is considered a real alternative for the treatment of Chagas disease.
Keywords: Chemotherapy, Chagas disease, Trypanosoma cruzi, High throughput screening, C14α-demethylase inhibitors, nitroheterocycles, azoles.
Current Topics in Medicinal Chemistry
Title:Stairway to Heaven or Hell? Perspectives and Limitations of Chagas Disease Chemotherapy
Volume: 16 Issue: 20
Author(s): Kelly Salomao, Rubem Figueiredo Sadok Menna-Barreto and Solange Lisboa de Castro
Affiliation:
Keywords: Chemotherapy, Chagas disease, Trypanosoma cruzi, High throughput screening, C14α-demethylase inhibitors, nitroheterocycles, azoles.
Abstract: In this review, we intend to provide a general view of the evolution of experimental studies in the area of chemotherapy for Chagas disease. We can follow the process of drug development through three phases. The first phase began almost at the same time as the discovery made by Carlos Chagas and proceeds to 1970, during which time an extensive list of compounds was subjected to preclinical and clinical trials. The second phase began with the introduction of nifurtimox and benznidazole into the clinical setting, followed with the search for alternative drugs. In this phase, a dichotomy existed between rational and empirical approaches in preclinical studies. The third phase began with the unravelling of the T. cruzi genome. The development of transgenic parasites has allowed the development of solid HTS protocols, and the establishment of bioluminescent T. cruzi has allowed in vivo drug evaluations using a reduced number of animals. Among the wide variety of compounds subjected to preclinical studies, we have discovered azolic and non-azolic inhibitors of sterol C14α-demethylase (CYP51) and nitro compounds. Two compounds evaluated during the second phase, namely, MK-436 and allopurinol, could be revisited. Clinical studies of posaconazole and E1224 yielded disappointing results, and it is critical to understand the reason for their failure as a monotherapy. Currently, the combination and repositioning of drugs with different mechanisms of action are complementary approaches. The use of drug combinations, particularly those of nitro compounds with CYP51 inhibitors, is considered a real alternative for the treatment of Chagas disease.
Export Options
About this article
Cite this article as:
Salomao Kelly, Figueiredo Sadok Menna-Barreto Rubem and Lisboa de Castro Solange, Stairway to Heaven or Hell? Perspectives and Limitations of Chagas Disease Chemotherapy, Current Topics in Medicinal Chemistry 2016; 16 (20) . https://dx.doi.org/10.2174/1568026616666160413125049
DOI https://dx.doi.org/10.2174/1568026616666160413125049 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Contribution of ALDH2 Polymorphism to Alcoholism-Associated Hypertension
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Update on the Adverse Effects of Clozapine: Focus on Myocarditis
Current Drug Safety Angiotensin-Converting Enzyme Inhibitors: Mechanisms of Action and Implications In Anesthesia Practice
Current Pharmaceutical Design Molecular Pathologies of and Enzyme Replacement Therapies for Lysosomal Diseases
CNS & Neurological Disorders - Drug Targets Pompe Disease and Autophagy: Partners in Crime, or Cause and Consequence?
Current Medicinal Chemistry The Fetal Cardiac Function
Current Cardiology Reviews Peroxisome Proliferator-Activated Receptor γ Agonists as Insulin Sensitizers: From the Discovery to Recent Progress
Current Topics in Medicinal Chemistry Heart Disease Induced by AAS Abuse, Using Experimental Mice/Rats Models and the Role of Exercise-Induced Cardiotoxicity
Mini-Reviews in Medicinal Chemistry Novel Strategies for the Detection of Systolic and Diastolic Heart Failure
Current Cardiology Reviews Beta-Blockers are Associated with Decreased In-Hospital Mortality and Stroke in Acute Decompensated Heart Failure: Findings from a Retrospective Analysis of a 22-Year Registry in the Middle East (1991-2013)
Current Vascular Pharmacology Cardiac Amyloidosis Responding to Bortezomib: Case Report and Review of Literature
Current Cardiology Reviews Biomarkers in Lone Atrial Fibrillation-An Additional ‘Fine Tuning’ of Risk?
Current Pharmaceutical Design Malignant Hypertension: A Rare Problem or is it Underdiagnosed?
Current Vascular Pharmacology New Insights into the Surgical Management of Tetralogy of Fallot: Physiological Fundamentals and Clinical Relevance
Current Pediatric Reviews Perinatal and Neonatal Outcomes of Lithium-Treated and Untreated Bipolar Women During Pregnancy: A Review of Present Literature
Current Psychopharmacology Health Benefits of Honey: Implications for Treating Cardiovascular Diseases
Current Nutrition & Food Science Respiratory Tract Manifestations of Rheumatic Diseases in Children
Current Respiratory Medicine Reviews Peripartum Cardiomyopathy: Current State of Knowledge, New Developments and Future Directions
Current Cardiology Reviews MDMA Toxicity and Pathological Consequences: A Review About Experimental Data and Autopsy Findings
Current Pharmaceutical Biotechnology The Adult Patient with Eisenmenger Syndrome: A Medical Update After Dana Point Part I: Epidemiology, Clinical Aspects and Diagnostic Options
Current Cardiology Reviews