Man-Chin, C.(Chung)

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    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.
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    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.