Addition of thiols to o-quinone methide: New 2-hydroxy-3-phenylsulfanylmethyl[1,4]naphthoquinones and their activity against the human malaria parasite Plasmodium falciparum (3D7)

Sharma, Abhinay; Santos, Isabela O.; Gaur, Pratibha; Ferreira, Vı́tor F.; Garcia, Célia Regina da Silva; Rocha, David R. da

doi:10.1016/j.ejmech.2012.10.052

Cited by 72 publications

(35 citation statements)

References 26 publications

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“…Corroborating the study of Sharma and co-workers [9], our most promising compounds also demonstrated the two phenyl groups at R 1 and R 2 , but in contrast to Plasmodium , the antileishmanial activity was not enhanced when the p -nitro group was used as a substituent at R1. Furthermore, the presence of the two phenyl groups at R1 and R 2 was mandatory to the anti-amastigote effect in our 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones, since the increased hydrophobicity possibly enhanced the penetration into macrophages or affected specific enzymes of the intracellular stage of the parasite.…”

Section: Discussionsupporting

confidence: 77%

“…Other naphtoquinones as buparvaquone (2-((4-tert-Butylcyclohexyl)methyl)-3-hydroxy-1,4-naphthoquinone), a veterinary drug against the protozoan parasite Theileria spp., has been found to be a promising lead against Leishmania spp, with IC 50 values in the range of 0.005 and 0.12 µM against L. ( L. ) donovani [18]–[19]. The synthesis of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones and their activity against the protozoan parasite Plasmodium falciparum was recently reported by Sharma and co-workers [9] and directed us to evaluate their potential in vitro activity against the etiologic agent of visceral leishmaniasis in Brazil and the Mediterranean region, the L. ( L. ) infantum .…”

Section: Discussionmentioning

confidence: 99%

“…This reaction explores in situ generation of o -quinonemethides ( o -QM) via the Knoevenagel condensation reaction between lawsone and formaldehyde [9].…”

Section: Methodsmentioning

confidence: 99%

“…Among the 1,4-naphthoquinone derivatives in literature, some promising antimalarials have been described [7]–[9]. Some other series of 1,4-naphthoquinone derivatives have also been widely evaluated against Mycobacterium tuberculosis [10], Plasmodium falciparum [9], and as molluscicidal candidates against Biomphalaria glabrata [11]. A number of reports have also shown the antiprotozoal potential of 1,4-naphthoquinone derivatives against Trypanosoma cruzi and Leishmania ( L. ) donovani [12]–[13].…”

Section: Introductionmentioning

confidence: 99%

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Potential of 2-Hydroxy-3-Phenylsulfanylmethyl-[1,4]-Naphthoquinones against Leishmania (L.) infantum: Biological Activity and Structure-Activity Relationships

et al. 2014

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Naphtoquinones have been used as promising scaffolds for drug design studies against protozoan parasites. Considering the highly toxic and limited therapeutic arsenal, the global negligence with tropical diseases and the elevated prevalence of co-morbidities especially in developing countries, the parasitic diseases caused by various Leishmania species (leishmaniasis) became a significant public health threat in 98 countries. The aim of this work was the evaluation of antileishmanial in vitro potential of thirty-six 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones obtained by a three component reaction of lawsone, the appropriate aldehyde and thiols adequately substituted, exploiting the in situ generation of o-quinonemethides (o-QM) via the Knoevenagel condensation. The antileishmanial activity of the naphthoquinone derivatives was evaluated against promastigotes and intracellular amastigotes of Leishmania (Leishmania) infantum and their cytotoxicity was verified in mammalian cells. Among the thirty-six compounds, twenty-seven were effective against promastigotes, with IC50 values ranging from 8 to 189 µM; fourteen compounds eliminated the intracellular amastigotes, with IC50 values ranging from 12 to 65 µM. The compounds containing the phenyl groups at R1 and R2 and with the fluorine substituent at the phenyl ring at R2, rendered the most promising activity, demonstrating a selectivity index higher than 15 against amastigotes. A QSAR (quantitative structure activity relationship) analysis yielded insights into general structural requirements for activity of most compounds in the series. Considering the in vitro antileishmanial potential of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones and their structure-activity relationships, novel lead candidates could be exploited in future drug design studies for leishmaniasis.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

“…This reaction explores in situ generation of o -quinonemethides ( o -QM) via the Knoevenagel condensation reaction between lawsone and formaldehyde [9].…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Potential of 2-Hydroxy-3-Phenylsulfanylmethyl-[1,4]-Naphthoquinones against Leishmania (L.) infantum: Biological Activity and Structure-Activity Relationships

et al. 2014

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“…1 Osim u tu svrhu, u literaturi su opisane brojne druge primjene QM-a, npr. kao antimalarika, 16 inhibitora mitohondrijske respiracije, 17 inhibitora glukuronidaze 18 te za detekciju fiziološki važnih tiola. 19 Važna primjena tih reaktivnih međuprodukata zauzima svoje mjesto u organskoj sintezi.…”

Section: 8unclassified

Kinon-metidi (I. dio): Reaktivni međuprodukti u kemiji fenola i njihova primjena u organskoj sintezi

2017

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Ovo djelo je dano na korištenje pod Creative Commons Attribution 4.0International LicenseInstitut Ruđer Bošković, Bijenička cesta 54, 10 000 Zagreb Sažetak Kinon-metidi (QM, naziv po IUPAC-u: kinometani) su reaktivni međuprodukti koji zauzimaju vrlo značajno mjesto u organskoj kemiji. Njihova primjena u organskoj sintezi je veoma velika, što je dovelo do razvoja velikog broja metoda za njihovo generiranje. Korisni su i u stereoselektivnim reakcijama, čime im je otvoren put za primjenu u totalnoj sintezi, nerijetko struktura koje su već pokazale značajnu biološku aktivnost. Ovim pregledom dan je uvid u metode sintetskog (termičkog) generiranja QM-a te njihovu primjenu u organskoj sintezi, s osvrtom na biološka svojstva samih QM-a ili produkata koji se iz njih dobivaju u sintezi. Ključne riječi Kinon-metidi, derivati fenola, termičko generiranje kinon-metida, kinon-metidi u organskoj sintezi, antiproliferativna aktivnost* Autor za dopisivanje: dr. sc. Đani Škalamera e-pošta: Djani.Skalamera@irb.hr ** Iako IUPAC više ne preporučuje upotrebu naziva kinon-metid, već preporučuje kinometan, autori ovog pregleda odlučili su zadržati stari naziv kinon-metid. Razlog tome je ponajprije usklađenost ovog članka sa svom ostalom relevantnom i recentnom literaturom o kinon-metidima, koja se koristi upravo tim nazivom. 354Đ. ŠKALAMERA et al.: Kinon-metidi (I. dio): Reaktivni međuprodukti u kemiji fenola…, (2017) 353−372 Osim osnovnih (roditeljskih) QM-a 1-3, u literaturi je uobičajeno kinon-metidima nazivati i sve ostale spojeve koji u svojoj strukturi sadrže metilensku i karbonilnu skupinu u vinilognom položaju. Tako se kinon-metidima nazivaju i derivati srodni m-QM-u 2, uobičajeni kod spojeva kod kojih zbog nemogućnosti konjugacije između metilenske skupine i kisika odgovarajući QM ima zwitterionski ili biradikalski karakter. Primjeri za navedene slučajeve prikazani su slikom 3.Slika 3 -Primjer neutralnog 6 2a i zwitterionskog 7 21 QM-a Fig. 3 -Example of neutral 6 2a and zwitterionic 7 21 QM Svojstva i kemijska reaktivnost kinon-metidaQM su reaktivne kratkoživuće vrste, vremena života tipično od <1 ns pa do nekoliko minuta, te je stoga za njihovo proučavanje potrebno primjenjivati tehnike tranzijentne spektroskopije, primjerice lasersku pulsnu fotolizu (LFP, od engl. laser flash photolysis). QM reagiraju s elektrofilima preko kisikova atoma, na način koji je tipičan za fenolate, a s nukleofilima reagiraju na metilenskom položaju pri čemu nastaju produkti Michaelove adicije 10 (shema 1). Kako su QM znatno reaktivniji od običnih enona kakvi su npr. α,β-nezasi eni ketoni, oni mogu reagirati i u [4+2] cikloadicijskim reakcijama (Diels-Alder) s dienofilima bogatim elektronima daju i kao produkte derivate kromana 9 (shema 1).Rearomatizacija koja se događa u reakciji adicije ujedno je i pokretačka sila navedenih reakcija. Supstituenti na QM znatno utječu na brzinu reakcija, te tako mogu utjecati na duljinu vremena života QM-a. 22 Obično su QM sami po sebi elektronski siromašni, pa će zbog toga elektron-odvlačeće skupine djelo...

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Organocatalytic Chemoselective C4‐Benzylation of 5‐Aminopyrazoles

Natarajan,

Kanchithalaivan,

Chatterjee

et al. 2024

Asian J Org Chem

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The first chemoselective C4‐benzylation of 5‐aminopyrazoles, utilizing a 3 mol% squaric acid catalyst, is disclosed. In this process, ortho‐quinone methides are efficiently generated from 2‐hydroxybenzyl alcohols in water under mild conditions. This method successfully delivers a wide range of C4‐benzylated 5‐aminopyrazoles, achieving moderate to excellent yields while demonstrating high chemoselectivity, which is further confirmed by mechanistic studies. Notably, the protocol uses water as an eco‐friendly solvent, requires a low organocatalyst loading, and eliminates the need for column chromatography.

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Addition of thiols to o-quinone methide: New 2-hydroxy-3-phenylsulfanylmethyl[1,4]naphthoquinones and their activity against the human malaria parasite Plasmodium falciparum (3D7)

Cited by 72 publications

References 26 publications

Potential of 2-Hydroxy-3-Phenylsulfanylmethyl-[1,4]-Naphthoquinones against Leishmania (L.) infantum: Biological Activity and Structure-Activity Relationships

Potential of 2-Hydroxy-3-Phenylsulfanylmethyl-[1,4]-Naphthoquinones against Leishmania (L.) infantum: Biological Activity and Structure-Activity Relationships

Kinon-metidi (I. dio): Reaktivni međuprodukti u kemiji fenola i njihova primjena u organskoj sintezi

Organocatalytic Chemoselective C4‐Benzylation of 5‐Aminopyrazoles

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