On the Search for Potential Antimycobacterial Drugs: Synthesis of Naphthoquinoidal, Phenazinic and 1,2,3-Triazolic Compounds and Evaluation Against<i>Mycobacterium tuberculosis</i>

Jardim, Guilherme A. M.; Cruz, Eduardo H. G. da; Valença, Wagner O.; Resende, Jarbas M.; Rodrigues, Bernardo L.; Ramos, Daniela Fernandes; Oliveira, Ronaldo N. de; Silva, Pedro E. A.; Júnior, Eufrânio N. da Silva

doi:10.5935/0103-5053.20150067

Cited by 11 publications

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“…Thus, both highlight the potential of naphthoquinones in the search for new anti-TB drugs. Our research group has developed several studies with a focus on new antimicrobial agents and, although other studies have reported the activity of other naphthoquinone derivatives, including for resistant strains, their mechanism of action is still uncertain ( Coelho et al, 2010 ; Jardim et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Naphthoquinone Derivatives as Scaffold to Develop New Drugs for Tuberculosis Treatment

et al. 2018

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Despite being a curable disease, tuberculosis (TB) remains a public health problem worldwide mainly due to lengthy treatment, as well as its toxic effects, TB/HIV co-infection and the emergence of resistant Mycobacterium tuberculosis strains. These barriers reinforcing the need for development of new antimicrobial agents, that ideally should reduce the time of treatment and be active against susceptible and resistant strains. Quinones are compounds found in natural sources and among them, the naphthoquinones show antifungal, antiparasitic, and antimycobacterial activity. Thus, we evaluated the potential antimycobacterial activity of six 1,4-naphthoquinones derivatives. We determined the minimum inhibitory concentration (MIC) of the compounds against three M. tuberculosis strains: a pan-susceptible H37Rv (ATCC 27294); one mono-resistant to isoniazid (ATCC 35822); and one mono-resistant to rifampicin (ATCC 35838); the cytotoxicity in the J774A.1 (ATCC TIB-67) macrophage lineage; performed in silico analysis about absorption, distribution, metabolism, and excretion (ADME) and docking sites. All evaluated naphthoquinones were active against the three strains with MIC between 206.6 and 12.5 μM, and the compounds with lower MIC values have also showed low cytotoxicity. Moreover, two naphthoquinones derivatives 5 and 6 probably do not exhibit cross resistance with isoniazid and rifampicin, respectively, and regarding ADME analysis, no compound violated the Lipinski’s rule-of-five. Considering the set of findings in this study, we conclude that these naphthoquinones could be promising scaffolds to develop new therapeutic strategies to TB.

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Section: Discussionmentioning

confidence: 99%

Naphthoquinone Derivatives as Scaffold to Develop New Drugs for Tuberculosis Treatment

et al. 2018

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“…The benzo[ a ]phenazines were prepared following the methodology previously described by our group (Jardim et al., 2015). The compounds, herein, studied are outlined in Scheme 1.…”

Section: Methodsmentioning

confidence: 99%

“…For at least 10 years, the research groups involved in this study have concentrated efforts in the continuous search for new scaffolds for the treatment of mycobacteriosis (Cantos et al., 2012; Carneiro et al., 2011; Moura et al., 2012; Reis et al., 2019). Considering the known anti‐ M. tuberculosis potential of phenazines (Jardim et al., 2015), the multidrug resistance concern, and the importance of developing new rational strategies against TB, studies combining these topics become increasingly necessary.…”

Section: Introductionmentioning

confidence: 99%

Benzo[a]phenazine derivatives: Promising scaffolds to combat resistant Mycobacteriumtuberculosis

et al. 2021

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The continuous emergence of resistant Mycobacterium tuberculosis keeps tuberculosis (TB) treatment options still insufficient, and new therapeutic alternatives are urgently needed. Considering the antimycobacterial activity of phenazine derivatives previously reported by our research group, we aimed to explore possible applications to circumvent the resistance in M. tuberculosis. Firstly, we evaluated the antimicrobial activity of seven benzo[a]phenazine derivatives against eleven M. tuberculosis strains: ten resistant and one susceptible (H37Rv). Then, we determined the cytotoxicity of benzo[a]phenazine derivatives and investigated the possible mechanism of action of the most promising compound. Among them, compound 10 was the only one active against all strains evaluated, with a minimum inhibitory concentration between 18.3 and 146.5 µM. For some resistant strains, this compound showed antimicrobial activity higher than rifampicin and it was also active against MDR strains, indicating an absence of cross‐resistance with anti‐TB drugs. Also, 10 showed a pharmacological safety for further in vivo studies and its mechanism of action seems to be related to oxidative stress. Thus, our findings indicate that benzo[a]phenazine derivatives are promising scaffolds for the development of new anti‐TB drugs, mainly focusing on the treatment of resistant TB cases.

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“…Some outstanding drug discovery programmes are widely used to find leading compounds, based on and inspired by the molecular modifications of natural products. Recent studies have demonstrated the potential of this approach for the discovery of new chemical entities in the treatment of neglected diseases (Carneiro et al., ; Cassamale et al., ; Costa et al., ; Dubar, Khalife, Brocard, Dive & Biot, ; Ferreira, ; Gomes et al., ; Jardim et al., ; Silva Júnior, Jardim, Menna‐Barreto & Castro, ; Varela et al., ; Zingales et al., ).…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and antitrypanosomatid activities of 3,5‐diaryl‐isoxazole analogues based on neolignans veraguensin, grandisin and machilin G

et al. 2018

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Using bioisosterism as a medicinal chemistry tool, 16 3,5-diaryl-isoxazole analogues of the tetrahydrofuran neolignans veraguensin, grandisin and machilin G were synthesized via 1,3-dipolar cycloaddition reactions, with yields from 43% to 90%. Antitrypanosomatid activities were evaluated against Trypanosoma cruzi, Leishmania (L.) amazonensis and Leishmania (V.) braziliensis. All compounds were selective for the Leishmania genus and inactive against T. cruzi. Isoxazole analogues showed a standard activity on both promastigotes of L. amazonensis and L. braziliensis. The most active compounds were 15, 16 and 19 with IC 50 values of 2.0, 3.3 and 9.5 μM against L. amazonensis and IC 50 values of 1.2, 2.1 and 6.4 μM on L. braziliensis, respectively. All compounds were noncytotoxic, showing lower cytotoxicity (>250 μM) than pentamidine (78.9 μM). Regarding the structure-activity relationship (SAR), the methylenedioxy group was essential to antileishmanial activity against promastigotes. Replacement of the tetrahydrofuran nucleus by an isoxazole core improved the antileishmanial activity. K E Y W O R D S bioisosterism, cycloaddition [3+2], isoxazole, neolignans 314 | TREFZGER ET al.

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On the Search for Potential Antimycobacterial Drugs: Synthesis of Naphthoquinoidal, Phenazinic and 1,2,3-Triazolic Compounds and Evaluation AgainstMycobacterium tuberculosis

Cited by 11 publications

References 0 publications

Naphthoquinone Derivatives as Scaffold to Develop New Drugs for Tuberculosis Treatment

Naphthoquinone Derivatives as Scaffold to Develop New Drugs for Tuberculosis Treatment

Benzo[a]phenazine derivatives: Promising scaffolds to combat resistant Mycobacteriumtuberculosis

Design, synthesis and antitrypanosomatid activities of 3,5‐diaryl‐isoxazole analogues based on neolignans veraguensin, grandisin and machilin G

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