{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T10:56:13Z","timestamp":1772189773250,"version":"3.50.1"},"reference-count":64,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,11,6]],"date-time":"2021-11-06T00:00:00Z","timestamp":1636156800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["project UID\/QUI\/00313\/2020"],"award-info":[{"award-number":["project UID\/QUI\/00313\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UI\/BD\/150859\/2021"],"award-info":[{"award-number":["UI\/BD\/150859\/2021"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["SFRH\/BPD\/115697\/2016"],"award-info":[{"award-number":["SFRH\/BPD\/115697\/2016"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>In this work, co-crystal screening was carried out for two important dihydrofolate reductase (DHFR) inhibitors, trimethoprim (TMP) and pyrimethamine (PMA), and for 2,4-diaminopyrimidine (DAP), which is the pharmacophore of these active pharmaceutical ingredients (API). The isomeric pyridinecarboxamides and two xanthines, theophylline (THEO) and caffeine (CAF), were used as co-formers in the same experimental conditions, in order to evaluate the potential for the pharmacophore to be used as a guide in the screening process. In silico co-crystal screening was carried out using BIOVIA COSMOquick and experimental screening was performed by mechanochemistry and supported by (solid + liquid) binary phase diagrams, infrared spectroscopy (FTIR) and X-ray powder diffraction (XRPD). The in silico prediction of low propensities for DAP, TMP and PMA to co-crystallize with pyridinecarboxamides was confirmed: a successful outcome was only observed for DAP + nicotinamide. Successful synthesis of multicomponent solid forms was achieved for all three target molecules with theophylline, with DAP co-crystals revealing a greater variety of stoichiometries. The crystalline structures of a (1:2) TMP:THEO co-crystal and of a (1:2:1) DAP:THEO:ethyl acetate solvate were solved. This work demonstrated the possible use of the pharmacophore of DHFR inhibitors as a guide for co-crystal screening, recognizing some similar trends in the outcome of association in the solid state and in the molecular aggregation in the co-crystals, characterized by the same supramolecular synthons.<\/jats:p>","DOI":"10.3390\/molecules26216721","type":"journal-article","created":{"date-parts":[[2021,11,7]],"date-time":"2021-11-07T20:41:14Z","timestamp":1636317674000},"page":"6721","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Dihydrofolate Reductase Inhibitors: The Pharmacophore as a Guide for Co-Crystal Screening"],"prefix":"10.3390","volume":"26","author":[{"given":"Jo\u00e3o A.","family":"Baptista","sequence":"first","affiliation":[{"name":"CQC, Departamento de Qu\u00edmica, Universidade de Coimbra,3004-535 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5782-8819","authenticated-orcid":false,"given":"M\u00e1rio T. S.","family":"Rosado","sequence":"additional","affiliation":[{"name":"CQC, Departamento de Qu\u00edmica, Universidade de Coimbra,3004-535 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1263-9034","authenticated-orcid":false,"given":"Ricardo A. E.","family":"Castro","sequence":"additional","affiliation":[{"name":"CQC, Departamento de Qu\u00edmica, Universidade de Coimbra,3004-535 Coimbra, Portugal"},{"name":"Faculdade de Farm\u00e1cia, Universidade de Coimbra,3000-548 Coimbra, Portugal"}]},{"given":"Ant\u00f3nio O. L.","family":"\u00c9vora","sequence":"additional","affiliation":[{"name":"CQC, Departamento de Qu\u00edmica, Universidade de Coimbra,3004-535 Coimbra, Portugal"},{"name":"Ctr Quim Estrutural, Faculdade Ci\u00eancias, Universidade de Lisboa,1749-016 Lisboa, Portugal"}]},{"given":"Teresa M. R.","family":"Maria","sequence":"additional","affiliation":[{"name":"CQC, Departamento de Qu\u00edmica, Universidade de Coimbra,3004-535 Coimbra, Portugal"}]},{"given":"Manuela","family":"Ramos Silva","sequence":"additional","affiliation":[{"name":"CfisUC, Departmento de F\u00edsica, Universidade de Coimbra, 3004-535 Coimbra, Portugal"}]},{"given":"Jo\u00e3o","family":"Canotilho","sequence":"additional","affiliation":[{"name":"CQC, Departamento de Qu\u00edmica, Universidade de Coimbra,3004-535 Coimbra, Portugal"},{"name":"Faculdade de Farm\u00e1cia, Universidade de Coimbra,3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5515-7721","authenticated-orcid":false,"given":"M. Ermelinda S.","family":"Eus\u00e9bio","sequence":"additional","affiliation":[{"name":"CQC, Departamento de Qu\u00edmica, Universidade de Coimbra,3004-535 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1080\/1120009X.1993.11741082","article-title":"History and future of antimicrobial diaminopyrimidines","volume":"5","author":"Then","year":"1993","journal-title":"J. Chemother."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S1359-6446(04)03308-2","article-title":"Targeting DHFR in parasitic protozoa","volume":"10","author":"Anderson","year":"2005","journal-title":"Drug Discov. Today"},{"key":"ref_3","first-page":"2535","article-title":"A study on dihydrofolate reductase and its inhibitors: A review","volume":"4","author":"Rao","year":"2013","journal-title":"Int. J. Pharm. Sci. 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