Paucar, R. (Rocío)
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- Design, synthesis and biological evaluation of Mannich base-type derivatives as potential agents for the treatment of Chagas disease(2019-07-12) Paucar, R. (Rocío); Pérez-Silanes, S. (Silvia); Moreno-de-Viguri, E. (Elsa)Chagas disease is considered a neglected tropical disease that continues to endanger millions of people around the world. The current chemotherapy presents some disadvantages such as variable antiparasitic activity, undesired side effects and/or long treatment duration. Therefore, the development of new drugs is mandatory. Several studies suggest the Mannich base derivatives as an attractive scaffold for new antiparasitic agents. Our research group has developed new Mannich bases with promising antichagasic activity. In this context, we have designed and synthesized forty-five Mannich bases to be tested against the T. cruzi parasite. The structural modifications made for the design of new derivatives have been made in order to obtain more effective and less toxic potential candidates to combat this parasitic disease. The novel Mannich bases containing the ferrocenyl, phenethylamines, anilines or piperazines groups, among others, have been tested against three different T. cruzi strains and forms. The cytotoxicity on Vero cells was also evaluated to determine their selectivity index. According to potency and SI, the most promising compounds were selected to evaluate the genotoxicity capacity via SOS/umu-test. Once demonstrated that these compounds are non-genotoxic, two compounds were selected for in vivo study in BALB/c mice. After the in vivo test, the non-mutagenic capacity of the compound with the most promising antichagasic profile was evaluated by the Ames test. On the other hand, the possible mechanism of action of these compounds was studied through the alteration of excreted metabolites by the parasite during glucose metabolism, the detection of mitochondrial alterations and the inhibition of superoxide dismutase. Finally, computational studies were executed to propose the binding mode of the studied compounds to iron superoxide dismutase enzyme. The results obtained will allow us to promote further preclinical studies of the most promising compounds.
- Challenges in Chagas Disease Drug Discovery: a review(2016) Pérez-Silanes, S. (Silvia); Paucar, R. (Rocío); Moreno-de-Viguri, E. (Elsa)Chagas disease or American trypanosomiasis is a neglected tropical disease caused by the parasite Trypanosoma cruzi. Although the number of infected individuals has decreased, about 6-7 million people are infected worldwide. The chemotherapy drugs currently used are limited to benznidazole and nifurtimox. They are effective in acute phase, congenital transmission and children with chronic infection; however, recent clinical trials have shown limitations in adults with chronic infection, presenting drawbacks during the treatment. Thus, there is an urgent need for new effective, safe and affordable drugs to fight against this complex disease. There were high expectations for azole derivatives as they appeared to be the most promising drugs for the treatment of Chagas disease during the last decade; however, the disappointing results obtained so far in clinical trials evidenced the lack of correlation between preclinical and clinical development. Therefore, the feedback obtained from these studies should define the starting point for addressing a roadmap for the drug discovery process in the fight against this disease. To tackle this challenge, it is important to keep in mind the drug target profile, already defined by panels of experts, and the coordinated work involving multi-disciplinary networks focusing not only on the discovery of new drugs but also on the standardization of the protocols that would allow acceleration in the Chagas disease drug discovery process.
- A Comparative Study of Conventional and Microwave‐Assisted Synthesis of Quinoxaline 1,4‐di‐N‐oxide N‐acylhydrazones Derivatives Designed as Antitubercular Drug Candidates(2017) Dos-Santos, J.L.(Jean Leandro); Pérez-Silanes, S. (Silvia); Paucar, R. (Rocío); Man-Chin, C.(Chung); Moreno-de-Viguri, E. (Elsa); Santivañez-Veliz, M. (Mery); Dos-Santos-Fernandes, G.F. (Guilherme-Felipe)Quinoxaline 1,4‐di‐N‐oxide (QdNO) and N‐acylhydrazone subunit are considered privileged scaffolds in medicinal chemistry because of its wide spectrum of biological activities, such as antibacterial, antitubercular, antiviral, anticancer, and antifungal. Beirut's reaction is the mostly commonly employed synthetic method to obtain QdNO; however, extended time, low yields, and byproduct formation are common features observed during the synthesis. Microwave‐assisted organic synthesis (MW) has gained popularity as an effective way to speed up chemical reactions, increasing yields and selectivity of a variety of reactions. Therefore, in an effort to synthesize compounds with potential to tuberculosis treatment, we reported herein the use of MW as a tool to obtain new QdNO derivatives containing the N‐acylhydrazone subunit. Four different synthetic routes were evaluated by using different benzofuroxan derivatives in the Beirut's reaction. The synthetic route D, which employed a dioxolan‐benzofuroxan derivative, has shown to be the best condition to obtain the desired hybrid quinoxaline. MW drastically reduces the reaction time to obtain all compounds compared to conventional heating. For compound 13, for example, the use of MW instead of conventional heating was able to reduce the reaction time in 192‐fold. In conclusion, the use of a benzofuroxan derivative without additional electrophilic sites besides N‐oxide nitrogen and the employment of the microwave‐assisted synthesis have proved to be the optimum condition to obtain quinoxaline 1,4‐di‐N‐oxide N‐acylhydrazone derivatives.
- Design, Synthesis and Characterization of N-oxide-containing Heterocycles with In vivo Sterilizing Antitubercular Activity(2017-10) Maringolo-Ribeiro, C.(Camila); Dos-Santos, J.L.(Jean Leandro); Wang, Y.(Yuehong); Franzblau, S.G. (Scott G.); Bento-da-Silva, P.(Patricia); De-Souza-Costa, C.A. (Carlos Alberto); Lazzarato, L. (Loretta); Chegaev, K. (Konstantin); Pérez-Silanes, S. (Silvia); Pavan, F.R.(Fernando Rogério); Paucar, R. (Rocío); Man-Chin, C.(Chung); Biancolino Marino, L.(Leonardo); Hunt, D.M.(Debbie M.); Guglielmo, S. (Stefano); De-Carvalho, L.P.S. (Luiz Pedro S.); Paiva Silva, C.S (Caio Sander); De-Souza, P.C (Paula Carolina); Cho, S.H. (Sang-Hyun); Moreno-de-Viguri, E. (Elsa); Longhin Bosquesi, P. (Priscila); Santivañez-Veliz, M. (Mery); Dos-Santos-Fernandes, G.F. (Guilherme-Felipe); Solcia, M.C. (María Cristina); Chorilli, M.(Marlus); Fruttero, R. (Roberta)Tuberculosis, caused by the Mycobacterium tuberculosis (Mtb), is the infectious disease responsible for the highest number of deaths worldwide. Herein, 22 new N-oxide- containing compounds were synthesized followed by in vitro and in vivo evaluation of their antitubercular potential against Mtb. Compound 8 was found to be the most promising compound, with MIC90 values of 1.10 and 6.62 μM against active and non- replicating Mtb, respectively. Additionally, we carried out in vivo experiments to confirm the safety and efficacy of compound 8; the compound was found to be orally bioavailable and highly effective leading to the reduction of the number of Mtb to undetected levels in a mouse model of infection. Microarray-based initial studies on the mechanism of action suggest that compound 8 blocks the process of translation. Altogether, these results indicated benzofuroxan derivative 8 to be a promising lead compound for the development of a novel chemical class of antitubercular drugs.