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Primaquine hybrids as promising antimycobacterial and antimalarial agents

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dc.contributor.authorPavić, Kristina
dc.contributor.authorPerković, Ivana
dc.contributor.authorPospíšilová, Šárka
dc.contributor.authorMachado, Marta
dc.contributor.authorFontinha, Diana
dc.contributor.authorPrudêncio, Miguel
dc.contributor.authorJampilek, Josef
dc.contributor.authorCoffey, Aidan
dc.contributor.authorEndersen, Lorraine
dc.contributor.authorRimac, Hrvoje
dc.contributor.authorZorc, Branka
dc.date.accessioned2021-12-02T15:56:47Z
dc.date.available2021-12-02T15:56:47Z
dc.date.issued2018
dc.description© 2017 Elsevier Masson SAS. All rights reserved.pt_PT
dc.description.abstractFour series of primaquine (PQ) derivatives were screened for antitubercular and antiplasmodial activity: amides 1a-k, ureas 2a-s, semicarbazides 3a-c and bis-ureas 4a-u. Antimycobacterial activity of PQ derivatives against Mycobacterium tuberculosis (MTB), M. avium complex (MAC) and M. avium subsp. paratuberculosis (MAP) were evaluated in vitro and compared with PQ and the standard antitubercular drugs. In general, the PQ derivatives showed higher potency than the parent compound. Most of the compounds of series 1 and 2 showed high activity against MAP, comparable or even higher than the relevant drug ciprofloxacin, and weak or no activity against MTB and MAC. bis-Trifluoromethylated cinnamamide 1k showed low cytotoxicity and high activity against all three Mycobacterium species and their activities were comparable or slightly higher than those of the reference drugs. PQ urea derivatives with hydroxyl, halogen and trifluoromethyl substituents on benzene ring 2f-p exerted very strong antimycobacterial activity towards all tested mycobacteria, stronger than PQ and the relevant standard drug(s). Unfortunately, these compounds had relatively high cytotoxicity, except bromo 2l and trifluoromethyl 2m, 2n derivatives. In general, meta-substituted derivatives were more active than analogues para-derivatives. Phenyl ureas were also more active than cycloalkyl or hydroxyalkyl ureas. Semicarbazide 3a showed similar activity as PQ, while the other two semicarbazides were inactive. Bis-urea derivatives 4 were generally less active than the urea derivatives sharing the same scaffold, differing only in the spacer type. Out of 21 evaluated bis-urea derivatives, only p-Cl/m-CF3 phenyl derivative 4p, benzhydryl derivatives 4t and 4u and bis-PQ derivative 4s showed high activity, higher than all three reference drugs. After comparison of activity and cytotoxicity, urea 2m and bis-urea 4u could be considered as the most promising agents. Antimalarial potential of PQ derivatives in vitro against the liver stage of P. berghei was evaluated as well. 3-(4-Chlorophenyl)-1-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]urea (4l) was the most active compound (IC50 = 42 nM; cytotoxicity/activity ratio >2000). Our results bring new insights into development of novel anti-TB and antimalarial compounds.pt_PT
dc.description.sponsorshipThis work has been fully supported by the Croatian Science Foundation under the project number IP-09-2014-1501, the Slovak Research and Development Agency, Grant No. APVV-0516-12 and by Science Foundation Ireland (SFI): Project Ref:12/R1/2335.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationEuropean journal of medicinal chemistry, 143, 769–779pt_PT
dc.identifier.doi10.1016/j.ejmech.2017.11.083pt_PT
dc.identifier.eissn1768-3254
dc.identifier.issn0223-5234
dc.identifier.urihttp://hdl.handle.net/10451/50256
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relation.publisherversionhttps://www.sciencedirect.com/journal/european-journal-of-medicinal-chemistrypt_PT
dc.subjectAntimycobacterial activitypt_PT
dc.subjectAntiplasmodial activitypt_PT
dc.subjectHybridpt_PT
dc.subjectPrimaquinept_PT
dc.titlePrimaquine hybrids as promising antimycobacterial and antimalarial agentspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage779pt_PT
oaire.citation.startPage769pt_PT
oaire.citation.titleEuropean Journal of Medicinal Chemistrypt_PT
oaire.citation.volume143pt_PT
person.familyNameFontinha
person.familyNamePrudêncio
person.givenNameDiana
person.givenNameMiguel
person.identifierhttps://scholar.google.pt/citations?user=zduN6wsAAAAJ&hl=pt-PT&oi=ao
person.identifier.ciencia-id6A17-C404-F33B
person.identifier.ciencia-id5511-16ED-48E0
person.identifier.orcid0000-0002-0046-648X
person.identifier.orcid0000-0003-1746-6029
person.identifier.scopus-author-id6603561872
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication4fa5980c-148c-4e44-a818-9e8d09245891
relation.isAuthorOfPublication80e4e74d-bf34-4a71-8530-cc3280543b65
relation.isAuthorOfPublication.latestForDiscovery4fa5980c-148c-4e44-a818-9e8d09245891

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