Design of hybrid molecules as antimycobacterial compounds: Synthesis of isoniazid-naphthoquinone derivatives and their activity against susceptible and resistant strains of Mycobacterium tuberculosis

Reis, Wallace J.; Bozzi, Ícaro A. O.; Ribeiro, Matheus F.; Halicki, Priscila Cristina Bartolomeu; Ferreira, Laís A.; Silva, Pedro Eduardo Almeida da; Ramos, Daniela Fernandes; Simone, C. A. De; Júnior, Eufrânio N. da Silva

doi:10.1016/j.bmc.2019.07.045

Cited by 19 publications

(12 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Finally, groups 7 and 8 are formed by hydrazo, imidazole, and oxazole derivatives [108][109][110][111]. The compounds in these groups were prepared from the quinones described above and represent our attempt to study quinone-derived heterocyclic compounds with biological activity against various microorganisms and their effectiveness against the virus that causes COVID-19.…”

Section: Assembly Of a Chemical Library For Virtual Screening Against Mpromentioning

confidence: 99%

Structure-based identification of naphthoquinones and derivatives as novel inhibitors of main protease Mpro and papain-like protease PLpro of SARS-CoV-2

Santos¹,

Kronenberger

Almeida

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

The worldwide COVID-19 pandemic caused by the coronavirus SARS-CoV-2 urgently demands novel direct antiviral treatments. The main protease (Mpro) and papain-like protease (PLpro) are attractive drug targets among coronaviruses due to their essential role in processing the polyproteins translated from the viral RNA. In the present work, we virtually screened 688 naphthoquinoidal compounds and derivatives against Mpro of SARS-CoV-2. Twenty-four derivatives were selected and evaluated in biochemical assays against Mpro using a novel fluorogenic substrate. In parallel, these compounds were also assayed with SARS-CoV-2 PLpro. Four compounds inhibited Mpro with half-maximal inhibitory concentration (IC50) values between 0.41 μM and 66 μM. In addition, eight compounds inhibited PLpro with IC50 ranging from 1.7 μM to 46 μM. Molecular dynamics simulations suggest stable binding modes for Mpro inhibitors with frequent interactions with residues in the S1 and S2 pockets of the active site. For two PLpro inhibitors, interactions occur in the S3 and S4 pockets. In summary, our structure-based computational and biochemical approach identified novel naphthoquinonal scaffolds that can be further explored as SARS-CoV-2 antivirals.

show abstract

Section: Assembly Of a Chemical Library For Virtual Screening Against Mpromentioning

confidence: 99%

Structure-based identification of naphthoquinones and derivatives as novel inhibitors of main protease Mpro and papain-like protease PLpro of SARS-CoV-2

Santos¹,

Kronenberger

Almeida

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Изониазид (гидразид 4-пиридинкарбоновой кислоты) является одним из первых антитуберкулёзных лекарственных веществ и используется как лекарство до сих пор. В связи с этим проводятся исследования по дизайну его улучшенных аналогов, в частности, направленные на получение его более липофильных производных с улучшенной способностью проникать через липидные мембраны микобактерий [3,4]. С другой стороны, способность микобактерий поглощать и превращать холестерин и некоторые другие стероиды в ряд продуктов окисления стероидного ядра и боковой цепи представляет интерес для разработки веществ с антимикобактериальной активностью в связи с появлением сообщений о важной роли этих превращений и осуществляющих их белков в вирулентности и выживаемости этих микроорганизмов [5,6].…”

Section: микобактерииunclassified

In silico modeling of izoniazid-steroid conjugates interactions with cytochromes P450 of mycobacteria and their bioconversion in vitro by the cells

et al. 2020

View full text Add to dashboard Cite

Molecular docking of four hydrazones of isoniazid with steroids (dehydroepiandrosterone, pregnenolone, 16α,17α-epoxypregnenolone, cholestenone) — IDHEA, IPRE, IEP5, ICHN, to mycobacterial cytochromes P450 was performed. The in silico study has shown than these hydrazones can be effectively bound to CYP121, CYP124, CYP125, CYP126A1, CYP130, and CYP51 with binding energy ranged from -9 kcal/mol to -12 kcal/mol. Calculations also demonstrated enhancement of passive lipid bilayer permeability with respect to isoniazid. In vitro IDHEA, IPRE, IEPR were found to undergo bioconversion into their 3-keto-4-en derivatives. This suggests their ability to penetrate into M. tuberculosis H37Rv cells. The results of this study are important in the context of understanding of specificity of binding of synthetic steroid derivatives to mycobacterial CYPs and indicate the possibility of using the steroid compounds studied by us as new ligands for these enzymes.

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

Design of hybrid molecules as antimycobacterial compounds: Synthesis of isoniazid-naphthoquinone derivatives and their activity against susceptible and resistant strains of Mycobacterium tuberculosis

Cited by 19 publications

References 64 publications

Structure-based identification of naphthoquinones and derivatives as novel inhibitors of main protease Mpro and papain-like protease PLpro of SARS-CoV-2

Structure-based identification of naphthoquinones and derivatives as novel inhibitors of main protease Mpro and papain-like protease PLpro of SARS-CoV-2

In silico modeling of izoniazid-steroid conjugates interactions with cytochromes P450 of mycobacteria and their bioconversion in vitro by the cells

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

Contact Info

Product

Resources

About