A Quinoxaline Derivative as a Potent Chemotherapeutic Agent, Alone or in Combination with Benznidazole, against Trypanosoma cruzi

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From: PLoS ONE(Vol. 9, Issue 1)
Publisher: Public Library of Science
Document Type: Article
Length: 7,942 words
Lexile Measure: 1580L

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Author(s): Jean Henrique da Silva Rodrigues 1, Tânia Ueda-Nakamura 2, Arlene Gonçalves Corrêa 3, Diego Pereira Sangi 3, Celso Vataru Nakamura 2,*

Introduction

The American trypanosomiasis, also known as Chagas' disease, is a major public health problem that affects more than 10 million people worldwide, mostly in Latin America where it is considered endemic. [1] The causative agent of Chagas' disease is the hemoflagellate protozoan Trypanosoma cruzi that belongs to Trypanosomatidae family. This taxon also includes other parasites that are responsible for relevant diseases, such as Trypanosoma brucei (Human African Trypanosomiasis) and Leishmania spp. (leishmaniasis). With regard to its clinical aspects, Chagas' disease has a variable presentation and progression. [2] Most infected patients will never develop any symptoms, characterizing the indeterminate form of chronic Chagas' disease. Approximately 30% of infected individuals will develop severe digestive or cardiac symptoms, [3] making this infection the most common cause of myocarditis worldwide. [4].

The available treatment for Chagas' disease is restricted to only two nitroheterocyclic compounds, benznidazole and nifurtmox, that have been used to treat Chagas' disease for more than 40 years. [5] Although both drugs are trypanocidal against all three forms of the parasite, their high systemic toxicity is important to consider, which can be expressed in a variety of symptoms, such as anorexia, nausea, headache, psychological disorders, polyneuropathies, and dermatitis. [6] Their efficacy is still considered low and restricted to acute manifestations of the disease. These drugs successfully cure approximately 20% and 80% of chronic and acute Chagas' disease patients, respectively. [7] Thus, new drugs and therapies should be sought for the treatment of Chagas' disease.

Several studies have been conducted to find new active compounds against T. cruzi . The search based on natural products is promising, with the possibility of screening a high number of plants and isolate active compounds with low toxicity. [8]-[9] Another approach that shows potential is the design and evaluation of synthetic compounds, either alone or in combination, against the parasite. [10]-[12] Among the groups of synthetic molecules, quinoxalines are a class of heterocyclic compounds that have been intensively studied for their biological activities, showing promising effect against bacteria, fungi, [13] tumors, [14] viruses, [15] and protozoa. [16]-[17] A library of new quinoxaline derivatives was recently tested against Leishmania peruviana and T. cruzi and showed interesting results. [18].

Combination therapy is an important way to improve the effectiveness of available drugs with different mechanisms of action in the treatment of several disorders, especially in the control of infectious diseases. [19] It is an approach that is currently used for the treatment of cancer, [20] osteoarthits, [21] tuberculosis, [22] acquired immune deficiency syndrome, [23] and opportunistic infections. [24] Compared with monotherapy, combination therapy presents higher cure rates, reduced treatment times, lower side effects, and delays in the selection of resistant parasites. [19].

Combination therapies based on the available drugs for Chagas' disease treatment, benznidazole and nifurtimox, and novel uses of old drugs, such as allopurinol, itraconazole, ketoconazole, and fluconazole, have been proposed as a promising therapeutic alternative...

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Gale Document Number: GALE|A478861922