N, N′, N″-trisubstituted guanidines: Synthesis, characterization and evaluation of their leishmanicidal activity

Santo, Rafael Dias do Espírito; Velásquez, Angela María Arenas; Passianoto, Luana Vitorino Gushiken; Lopera, Alex; Clementino, Leandro da Costa; Assis, Renata Pires; Baviera, Amanda Martins; Kalaba, Predrag; Santos, Fábio Neves dos; Eberlin, Marcos N.; Silva, Gil Valdo Jose da; Zehl, Martin; Lübec, Gert; Graminha, Márcia Aparecida Silva; Gonzalez, E R

doi:10.1016/j.ejmech.2019.03.032

Cited by 15 publications

(39 citation statements)

References 52 publications

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“…LQOF-G6 showed a 73% inhibitory activity against CPB with IC 50-CPB of 6.0 ± 0.2 μM. This is a highly relevant result, which differentiates LQOF-G6 from other guanidines of this series, such as the previously reported LQOF-G2 [ 24 ] . LQOF-G2 is a potent leishmanicidal compound in vivo against L. amazonensis ; however, it did not show inhibitory activity against Lm CPB2.8ΔCTE.…”

Section: Resultssupporting

confidence: 62%

“…In the process of this work, the structural characterizations of the molecules LQOF-G6 and LQOF-G32 were performed, initially by in-solution NMR, whose results are described in the supplementary material . The molecules LQOF-G1 and LQOF-G2 were previously reported [ 24 ].…”

Section: Resultsmentioning

confidence: 99%

“…( Z )- N -benzoyl- N ′-benzyl- N ″-(4-tertbutylphenyl) guanidine LQOF-G6 , LQOF-G1 –(4-nitrophenyl), and LQOF-G2 -(4-bromophenyl) guanidines were synthesized as previously reported [ 24 ]. The LQOF-G32 ( Z )- N -benzoyl- N ′-(2,4-dichlorobenzyl)- N ″-(4-bromophenyl)guanidine is a new guanidine that was prepared using the same procedure.…”

Section: Methodsmentioning

confidence: 99%

“…Leishmania amazonensis promastigotes (MPRO/BR/1972/M1841-LV-79) were maintained at 28 °C in liver-infusion tryptase medium (LIT) supplemented with heat-inactivated fetal bovine serum (iFBS), streptomycin (10 mg/mL), and penicillin (1000 U/mL) [ 24 , 32 , 33 ].…”

Section: Methodsmentioning

confidence: 99%

“…In vivo leishmanicidal activity of guanidine LQOF-G6 was performed as previously described [ 24 , 34 ]. Briefly, female BALB/c mice (20 to 25 g; 5 weeks old; CEMIB, UNICAMP) were subcutaneously inoculated at the right ear with ~10 7 infective promastigotes at the stationary growth phase of L. amazonensis .…”

Section: Methodsmentioning

confidence: 99%

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Novel Selective and Low-Toxic Inhibitor of LmCPB2.8ΔCTE (CPB) One Important Cysteine Protease for Leishmania Virulence

et al. 2022

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Leishmaniasis is a highly prevalent, yet neglected disease caused by protozoan parasites of the genus Leishmania. In the search for newer, safer, and more effective antileishmanial compounds, we herein present a study of the mode of action in addition to a detailed structural and biological characterization of LQOF-G6 [N-benzoyl-N′-benzyl-N″-(4-tertbutylphenyl)guanidine]. X-ray crystallography and extensive NMR experiments revealed that LQOF-G6 nearly exclusively adopts the Z conformation stabilized by an intramolecular hydrogen bond. The investigated guanidine showed selective inhibitory activity on Leishmania major cysteine protease LmCPB2.8ΔCTE (CPB) with ~73% inhibition and an IC50-CPB of 6.0 µM. This compound did not show any activity against the mammalian homologues cathepsin L and B. LQOF-G6 has been found to be nontoxic toward both organs and several cell lines, and no signs of hepatotoxicity or nephrotoxicity were observed from the analysis of biochemical clinical plasma markers in the treated mice. Docking simulations and experimental NMR measurements showed a clear contribution of the conformational parameters to the strength of the binding in the active site of the enzyme, and thus fit the differences in the inhibition values of LQOF-G6 compared to the other guanidines. Furthermore, the resulting data render LQOF-G6 suitable for further development as an antileishmanial drug.

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Section: Resultssupporting

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Novel Selective and Low-Toxic Inhibitor of LmCPB2.8ΔCTE (CPB) One Important Cysteine Protease for Leishmania Virulence

et al. 2022

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Copper‐Catalyzed Guanylation by Ring Extension of 4‐Hydroxyquinazoline for the Synthesis of Quinazolino[3,2‐a]quinazolinones

Palavong,

Arunkirirote,

Tummatorn

et al. 2023

Asian J Org Chem

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This work reports a new method for the synthesis of quinazolino[3,2‐a]quinazolinone derivatives under ligand‐free copper‐catalyzed guanylation through C−H functionalization. The reaction provides a convenient protocol which can be applied to a broad range of substrates providing the corresponding products in good to excellent yields. Additionally, this process provides a number of benefits, including minimal waste, rapid reaction times, and readily available starting material.

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Improved Synthetic Methodology, Substrate Scope and X‐ray Crystal Structure for N, N’‐disubstituted Guanidines

Elumalai,

Vaclav,

Visnes

et al. 2024

ChemistrySelect

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Guanidine is a privileged scaffold in drug discovery. Herein we report our investigations into the acid promoted amination of pyrimidine‐bearing cyanamide to produce N, N’‐disubstituted guanidines. Hydrochloric acid was found to be a suitable catalyst, and the substrate scope using conventional heating was investigated with 23 aniline derivatives. The highest yield was obtained with anilines having pKa in the range of 2–4. Further, a microwave synthesis was developed using 3‐chloroaniline as a model substrate increasing the yield from 68 to 93 %. The microwave method was especially suited for increasing yields with anilines having pKa > 3. The structure of the pyrimidine‐bearing guanidines was confirmed by NMR spectroscopy, and one representative compound has been evaluated by X‐ray crystallography, showing the trans‐isomer as the only tautomer in solid form.

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N, N′, N″-trisubstituted guanidines: Synthesis, characterization and evaluation of their leishmanicidal activity

Cited by 15 publications

References 52 publications

Novel Selective and Low-Toxic Inhibitor of LmCPB2.8ΔCTE (CPB) One Important Cysteine Protease for Leishmania Virulence

Novel Selective and Low-Toxic Inhibitor of LmCPB2.8ΔCTE (CPB) One Important Cysteine Protease for Leishmania Virulence

Copper‐Catalyzed Guanylation by Ring Extension of 4‐Hydroxyquinazoline for the Synthesis of Quinazolino[3,2‐a]quinazolinones

Improved Synthetic Methodology, Substrate Scope and X‐ray Crystal Structure for N, N’‐disubstituted Guanidines

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