000129623 001__ 129623
000129623 005__ 20250313085414.0
000129623 0247_ $$2doi$$a10.1016/j.ejmech.2021.113784
000129623 0248_ $$2sideral$$a126760
000129623 037__ $$aART-2021-126760
000129623 041__ $$aeng
000129623 100__ $$aSong L.
000129623 245__ $$aStructure-aided optimization of non-nucleoside M. tuberculosis thymidylate kinase inhibitors
000129623 260__ $$c2021
000129623 5060_ $$aAccess copy available to the general public$$fUnrestricted
000129623 5203_ $$aMycobacterium tuberculosis thymidylate kinase (MtTMPK) has emerged as an attractive target for rational drug design. We recently investigated new families of non-nucleoside MtTMPK inhibitors in an effort to diversify MtTMPK inhibitor chemical space. We here report a new series of MtTMPK inhibitors by combining the Topliss scheme with rational drug design approaches, fueled by two co-crystal structures of MtTMPK in complex with developed inhibitors. These efforts furnished the most potent MtTMPK inhibitors in our assay, with two analogues displaying low micromolar MIC values against H37Rv Mtb. Prepared inhibitors address new sub-sites in the MtTMPK nucleotide binding pocket, thereby offering new insights into its druggability. We studied the role of efflux pumps as well as the impact of cell wall permeabilizers for selected compounds to potentially provide an explanation for the lack of correlation between potent enzyme inhibition and whole-cell activity. © 2021 Elsevier Masson SAS
000129623 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttp://creativecommons.org/licenses/by-nc-nd/3.0/es/
000129623 590__ $$a7.088$$b2021
000129623 591__ $$aCHEMISTRY, MEDICINAL$$b5 / 63 = 0.079$$c2021$$dQ1$$eT1
000129623 592__ $$a1.054$$b2021
000129623 593__ $$aDrug Discovery$$c2021$$dQ1
000129623 593__ $$aPharmacology$$c2021$$dQ1
000129623 593__ $$aMedicine (miscellaneous)$$c2021$$dQ1
000129623 594__ $$a11.2$$b2021
000129623 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/acceptedVersion
000129623 700__ $$aMerceron R.
000129623 700__ $$aHulpia F.
000129623 700__ $$0(orcid)0000-0002-0111-4697$$aLucía A.$$uUniversidad de Zaragoza
000129623 700__ $$0(orcid)0000-0001-9233-5024$$aGracia B.$$uUniversidad de Zaragoza
000129623 700__ $$aJian Y.
000129623 700__ $$aRisseeuw M.D.P.
000129623 700__ $$aVerstraelen T.
000129623 700__ $$aCos P.
000129623 700__ $$0(orcid)0000-0003-2076-844X$$aAínsa J.A.$$uUniversidad de Zaragoza
000129623 700__ $$aBoshoff H.I.
000129623 700__ $$aMunier-Lehmann H.
000129623 700__ $$aSavvides S.N.
000129623 700__ $$aVan Calenbergh S.
000129623 7102_ $$11011$$2630$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cÁrea Microbiología
000129623 7102_ $$11011$$2X$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cProy. investigación HQA
000129623 773__ $$g225 (2021), 137842 [25 pp]$$pEur. j. med. chem.$$tEUROPEAN JOURNAL OF MEDICINAL CHEMISTRY$$x0223-5234
000129623 8564_ $$s2432445$$uhttps://zaguan.unizar.es/record/129623/files/texto_completo.pdf$$yPostprint
000129623 8564_ $$s1439317$$uhttps://zaguan.unizar.es/record/129623/files/texto_completo.jpg?subformat=icon$$xicon$$yPostprint
000129623 909CO $$ooai:zaguan.unizar.es:129623$$particulos$$pdriver
000129623 951__ $$a2025-03-13-08:43:51
000129623 980__ $$aARTICLE