{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T21:01:43Z","timestamp":1783458103361,"version":"3.55.0"},"reference-count":80,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,10,4]],"date-time":"2022-10-04T00:00:00Z","timestamp":1664841600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grand Challenges Africa","award":["GCA\/DD\/rnd3\/006"],"award-info":[{"award-number":["GCA\/DD\/rnd3\/006"]}]},{"name":"African Academy of Sciences (AAS)","award":["GCA\/DD\/rnd3\/006"],"award-info":[{"award-number":["GCA\/DD\/rnd3\/006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>New drugs are urgently needed for the treatment of human African trypanosomiasis (HAT). In line with our quest for novel inhibitors of trypanosomes, a small library of analogs of the antitrypanosomal hit (MMV675968) available at MMV as solid materials was screened for antitrypanosomal activity. In silico exploration of two potent antitrypanosomal structural analogs (7-MMV1578647 and 10-MMV1578445) as inhibitors of dihydrofolate reductase (DHFR) was achieved, together with elucidation of other antitrypanosomal modes of action. In addition, they were assessed in vitro for tentative inhibition of DHFR in a crude trypanosome extract. Their ADMET properties were also predicted using dedicated software. Overall, the two diaminoquinazoline analogs displayed approximately 40-fold and 60-fold more potency and selectivity in vitro than the parent hit, respectively (MMV1578445 (10): IC50 = 0.045 \u00b5M, SI = 1737; MMV1578467 (7): IC50 = 0.06 \u00b5M; SI = 412). Analogs 7 and 10 were also strong binders of the DHFR enzyme in silico, in all their accessible protonation states, and interacted with key DHFR ligand recognition residues Val32, Asp54, and Ile160. They also exhibited significant activity against trypanosome protein isolate. MMV1578445 (10) portrayed fast and irreversible trypanosome growth arrest between 4\u201372 h at IC99. Analogs 7 and 10 induced in vitro ferric iron reduction and DNA fragmentation or apoptosis induction, respectively. The two potent analogs endowed with predicted suitable physicochemical and ADMET properties are good candidates for further deciphering their potential as starting points for new drug development for HAT.<\/jats:p>","DOI":"10.3390\/molecules27196574","type":"journal-article","created":{"date-parts":[[2022,10,9]],"date-time":"2022-10-09T23:31:43Z","timestamp":1665358303000},"page":"6574","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Preliminary Structure\u2013Activity Relationship Study of the MMV Pathogen Box Compound MMV675968 (2,4-Diaminoquinazoline) Unveils Novel Inhibitors of Trypanosoma brucei brucei"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3387-4102","authenticated-orcid":false,"given":"Darline","family":"Dize","sequence":"first","affiliation":[{"name":"Antimicrobial and Biocontrol Agents Unit (AmBcAU), Laboratory for Phytobiochemistry and Medicinal Plants Studies, Department of Biochemistry, Faculty of Science, University of Yaound\u00e9 I, Yaound\u00e9 P.O. Box 812, Cameroon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8814-5241","authenticated-orcid":false,"given":"Rolland Bantar","family":"Tata","sequence":"additional","affiliation":[{"name":"Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6139, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigue","family":"Keumoe","sequence":"additional","affiliation":[{"name":"Antimicrobial and Biocontrol Agents Unit (AmBcAU), Laboratory for Phytobiochemistry and Medicinal Plants Studies, Department of Biochemistry, Faculty of Science, University of Yaound\u00e9 I, Yaound\u00e9 P.O. Box 812, Cameroon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2144-0710","authenticated-orcid":false,"given":"Rufin Marie","family":"Kouipou Toghueo","sequence":"additional","affiliation":[{"name":"Antimicrobial and Biocontrol Agents Unit (AmBcAU), Laboratory for Phytobiochemistry and Medicinal Plants Studies, Department of Biochemistry, Faculty of Science, University of Yaound\u00e9 I, Yaound\u00e9 P.O. Box 812, Cameroon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariscal Brice","family":"Tchatat","sequence":"additional","affiliation":[{"name":"Antimicrobial and Biocontrol Agents Unit (AmBcAU), Laboratory for Phytobiochemistry and Medicinal Plants Studies, Department of Biochemistry, Faculty of Science, University of Yaound\u00e9 I, Yaound\u00e9 P.O. Box 812, Cameroon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyrille Ngansop","family":"Njanpa","sequence":"additional","affiliation":[{"name":"Antimicrobial and Biocontrol Agents Unit (AmBcAU), Laboratory for Phytobiochemistry and Medicinal Plants Studies, Department of Biochemistry, Faculty of Science, University of Yaound\u00e9 I, Yaound\u00e9 P.O. Box 812, Cameroon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vianey Claire","family":"Tchuenguia","sequence":"additional","affiliation":[{"name":"Antimicrobial and Biocontrol Agents Unit (AmBcAU), Laboratory for Phytobiochemistry and Medicinal Plants Studies, Department of Biochemistry, Faculty of Science, University of Yaound\u00e9 I, Yaound\u00e9 P.O. Box 812, Cameroon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauve Tchokouaha","family":"Yamthe","sequence":"additional","affiliation":[{"name":"Antimicrobial and Biocontrol Agents Unit (AmBcAU), Laboratory for Phytobiochemistry and Medicinal Plants Studies, Department of Biochemistry, Faculty of Science, University of Yaound\u00e9 I, Yaound\u00e9 P.O. Box 812, Cameroon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3724-3527","authenticated-orcid":false,"given":"Patrick Valere Tsouh","family":"Fokou","sequence":"additional","affiliation":[{"name":"Antimicrobial and Biocontrol Agents Unit (AmBcAU), Laboratory for Phytobiochemistry and Medicinal Plants Studies, Department of Biochemistry, Faculty of Science, University of Yaound\u00e9 I, Yaound\u00e9 P.O. Box 812, Cameroon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7530-2113","authenticated-orcid":false,"given":"Beno\u00eet","family":"Laleu","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture, Route de Pr\u00e9-Bois 20, 1215 Meyrin, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Duffy","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture, Route de Pr\u00e9-Bois 20, 1215 Meyrin, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6861-7849","authenticated-orcid":false,"given":"Ozlem Tastan","family":"Bishop","sequence":"additional","affiliation":[{"name":"Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6139, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3147-364X","authenticated-orcid":false,"given":"Fabrice Fekam","family":"Boyom","sequence":"additional","affiliation":[{"name":"Antimicrobial and Biocontrol Agents Unit (AmBcAU), Laboratory for Phytobiochemistry and Medicinal Plants Studies, Department of Biochemistry, Faculty of Science, University of Yaound\u00e9 I, Yaound\u00e9 P.O. 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