Cyclohexene-fused 1,3-oxazines with selective antibacterial and antiparasitic action and low cytotoxic effects

Brito, Maria R. M.; Peláez, Walter José; Faillace, Martín S.; Militão, Gardênia Carmen Gadelha; Almeida, Jackson R.G.S.; Argüello, Gustavo A.; Szakonyi, Zsolt; Fülöp, Ferenc; Salvadori, M. C.; Teixeira, F. S.; Freitas, Rivelilson Mendes de; Pintó, Pedro; Mengarda, Ana C.; Silva, Marcos P.N.; Filho, Ademar A. Da Silva; Moraes, Josué de

doi:10.1016/j.tiv.2017.07.021

Cited by 41 publications

(23 citation statements)

References 37 publications

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“…Scanning electron microscopy images indicated that tegumental structure was altered in both male and female S. mansoni organisms and intensified progressively when the concentrations of spironolactone increased. These morphological alterations were similar to those reported in studies with other anthelmintic compounds (15,16). Likewise, it is known that praziquantel exhibits potent in vitro effects against schistosomes, and it causes extensive tegumental alterations in a concentration-dependent manner (17,18).…”

Section: Discussionsupporting

confidence: 85%

In Vitro and In Vivo Studies of Spironolactone as an Antischistosomal Drug Capable of Clinical Repurposing

Guerra

Silva

et al. 2019

Antimicrob Agents Chemother

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Schistosomiasis is a parasitic flatworm disease that infects over 200 million people worldwide, especially in poor communities. Treatment and control of the disease rely on just one drug, praziquantel. Since funding for drug development for poverty-associated diseases is very limited, drug repurposing is a promising strategy. In this study, from a screening of 13 marketed diuretics, we identified that spironolactone, a potassium-sparing diuretic, had potent antischistosomal effects on Schistosoma mansoni in vitro and in vivo in a murine model of schistosomiasis. In vitro, spironolactone at low concentrations (<10 µM) is able to alter worm motor activity and the morphology of adult schistosomes, leading to parasitic death. In vivo, oral treatment with spironolactone at a single dose (400 mg/kg) or daily for five consecutive days (100 mg/kg/day) in mice harboring either patent or prepatent infections significantly reduced worm burden, egg production, and hepato- and splenomegaly (P < 0.05 to P < 0.001). Taken together, with the safety profile of spironolactone, supported by its potential to affect schistosomes, these results indicate that spironolactone could be a potential treatment for schistosomiasis and make it promising for repurposing.

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Section: Discussionsupporting

confidence: 85%

In Vitro and In Vivo Studies of Spironolactone as an Antischistosomal Drug Capable of Clinical Repurposing

Guerra

Silva

et al. 2019

Antimicrob Agents Chemother

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“…A literature survey revealed that 1,3‐oxazine ring system is found in numerous pharmaceutical agents and other bioactive molecules . For example, PD‐102807 serves as a selective antagonist for the muscarinic acetylcholine receptor M4 .…”

Section: Introductionmentioning

confidence: 99%

Novel 1,3‐oxazine‐tetrazole hybrids as mushroom tyrosinase inhibitors and free radical scavengers: Synthesis, kinetic mechanism, and molecular docking studies

et al. 2018

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A variety of 5-(2H-tetrazol-5-yl)-4-thioxo-2-(substituted phenyl)-4,5-dihydro-1,3-oxazin-6-ones (3a-k) have been synthesized from 1,3-oxazine-5-carbonitriles (2a-k). The protocol represents an efficient, facile, and novel route from easily available precursors to unprecedented structures that share 1,3-oxazine and tetrazole motifs of utmost value. All the synthesized compounds (3a-k) were evaluated for their inhibitory potential against mushroom tyrosinase. Results revealed that all examined 1,3-oxazine-tetrazole hybrids exhibited significant tyrosinase inhibitory activity while compound 3d having 2-bromophenyl moiety was the most potent among the series with IC value 0.0371 ± 0.0018 μM as compared to the reference kojic acid (IC = 16.832 ± 0.73 μM). Inhibitory kinetics showed that compound 3d behaves as a competitive inhibitor. The molecular docking analysis was performed against target protein to investigate the binding mode. Moreover, compounds 3j and 3k displayed superior DPPH radical scavenging activity than other analogues.

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“…Cytotoxicity was also evaluated using Vero cells, a monkey kidney cell line obtained from the American Type Culture Collection (ATCC CCL-81; Manassas, VA). The cytotoxicity was determined by the 3-(4,5dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide (MTT) method according to a previously described procedure [ 16 , 17 ].…”

Section: Methodsmentioning

confidence: 99%

4-Phenyl-1,3-thiazole-2-amines as scaffolds for new antileishmanial agents

Rodrigues

Santos

Costa

et al. 2018

J Venom Anim Toxins Incl Trop Dis

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BackgroundThere is still a need for new alternatives in pharmacological therapy for neglected diseases, as the drugs available show high toxicity and parenteral administration. That is the case for the treatment of leishmaniasis, particularly to the cutaneous clinical form of the disease. In this study, we present the synthesis and biological screening of eight 4-phenyl-1,3-thiazol-2-amines assayed against Leishmania amazonensis. Herein we propose that these compounds are good starting points for the search of new antileishmanial drugs by demonstrating some of the structural aspects which could interfere with the observed activity, as well as suggesting potential macromolecular targets.MethodsThe compounds were easily synthesized by the methodology of Hantzsch and Weber, had their purities determined by Gas Chromatography-Mass spectrometry and assayed against the promastigote forms of Leishmania amazonensis as well as against two white cell lines (L929 and THP-1) and the monkey’s kidney Vero cells. PrestoBlue® and MTT viability assays were the methodologies applied to measure the antileishmanial and cytotoxic activities, respectively. A molecular modeling target fishing study was performed aiming to propose potential macromolecular targets which could explain the observed biological behavior.ResultsFour out of the eight compounds tested exhibited important anti-promastigote activity associated with good selectivity indexes when considering Vero cells. For the most promising compound, compound 6, IC50 against promastigotes was 20.78 while SI was 5.69. Compounds 3 (IC50: 46.63 μM; SI: 26.11) and 4 (IC50: 53.12 μM; SI: 4.80) also presented important biological behavior. A target fishing study suggested that S-methyl-5-thioadenosine phosphorylase is a potential target to these compounds, which could be explored to enhance activity and decrease the potential toxic side effects.ConclusionsThis study shows that 4-phenyl-1,3-thiazol-2-amines could be good scaffolds to the development of new antileishmanial agents. The S-methyl-5-thioadenosine phosphorylase could be one of the macromolecular targets involved in the action.Electronic supplementary materialThe online version of this article (10.1186/s40409-018-0163-x) contains supplementary material, which is available to authorized users.

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Cyclohexene-fused 1,3-oxazines with selective antibacterial and antiparasitic action and low cytotoxic effects

Cited by 41 publications

References 37 publications

In Vitro and In Vivo Studies of Spironolactone as an Antischistosomal Drug Capable of Clinical Repurposing

In Vitro and In Vivo Studies of Spironolactone as an Antischistosomal Drug Capable of Clinical Repurposing

Novel 1,3‐oxazine‐tetrazole hybrids as mushroom tyrosinase inhibitors and free radical scavengers: Synthesis, kinetic mechanism, and molecular docking studies

4-Phenyl-1,3-thiazole-2-amines as scaffolds for new antileishmanial agents

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