Publications

Calic P.P.S, Ashton T.D, Mansouri M, Loi K, Jarman K.E, Qiu D, Lehane A.M, Roy S, Rao G.P, Maity B, Wittlin S, Crespo B, Gamo F.J, Deni I, Fidock D.A, Chowdury M, de Koning-Ward T.F, Cowman A.F, Jackson P.F, Baud D, Brand S, Laleu B, Sleebs B.E. Optimization of pyrazolopyridine 4-carboxamides with potent antimalarial activity for which resistance is associated with the P. falciparum transporter ABCI3. Eur J Med Chem. 2024;276:116677. DOI: 10.1016/j.ejmech.2024.116677

Dziwornu G.A, Seanego D, Fienberg S, Clements M, Ferreira J, Sypu V.S, Samanta S, Bhana A.D, Korkor C.M, Garnie L.F, Teixeira N, Wicht K.J, Taylor D, Olckers R, Njoroge M, Gibhard L, Salomane N, Wittlin S, Mahato R, Chakraborty A, Sevilleno N, Coyle R, Lee M.C.S, Godoy L.C, Pasaje C.F, Niles J.C, Reader J, van der Watt M, Birkholtz L.M, Bolscher J.M, de Bruijni M.H.C, Coulson L.B, Basarab G.S, Ghorpade S.R, Chibale K. 2,8-disubstituted-1,5-naphthyridines as dual inhibitors of Plasmodium falciparum phosphatidylinositol-4-kinase and hemozoin formation with in vivo efficacy. J Med Chem. 2024;67(13):11401-11420. DOI: 10.1021/acs.jmedchem.4c01154

Edgar R.C.S, Malcolm T.R, Siddiqui G, Giannangelo C, Counihan N.A, Challis M, Duffy S, Chowdhury M, Marfurt J, Dans M, Wirjanata G, Noviyanti R, Daware K, Suraweera C.D, Price R.N, Wittlin S, Avery V.M, Drinkwater N, Charman S.A, Creek D.J, de Koning-Ward T.F, Scammells P.J, McGowan S. On-target, dual aminopeptidase inhibition provides cross-species antimalarial activity. mBio. 2024;15(6):e0096624. DOI: 10.1128/mbio.00966-24

Giannangelo C, Challis M.P, Siddiqui G, Edgar R, Malcolm T.R, Webb C.T, Drinkwater N, Vinh N, Macraild C, Counihan N, Duffy S, Wittlin S, Devine S.M, Avery V.M, De Koning-Ward T, Scammells P, McGowan S, Creek D.J. Chemoproteomics validates selective targeting of Plasmodium M1 alanyl aminopeptidase as an antimalarial strategy. Elife. 2024;13:RP92990. DOI: 10.7554/eLife.92990

Hellingman A, Sifoniou K, Buser T, Thommen B.T, Walz A, Passecker A, Collins J, Hupfeld M, Wittlin S, Witmer K, Brancucci N.M.B. Next generation chemiluminescent probes for antimalarial drug discovery. ACS Infect Dis. 2024;10(4):1286−1297. DOI: 10.1021/acsinfecdis.3c00707

Kolb B, Schmid F, Weng J, Altevogt L, Rebelo R.P, Wank B, Baro A, Zens A, Shekhar A, Bilitewski U, Sax S, Wittlin S, Taylor D, Müller R, Laschat S. Total synthesis of tosyl-samroiyotmycin A and its biological profiling. Chemistry. 2024(in press). DOI: 10.1002/chem.202403408

Lawong A, Gahalawat S, Ray S, Ho N, Han Y, Ward K.E, Deng X, Chen Z, Kumar A, Xing C, Hosangadi V, Fairhurst K.J, Tashiro K, Liszczak G, Shackleford D.M, Katneni K, Chen G, Saunders J, Crighton E, Casas A, Robinson J.J, Imlay L.S, Zhang X, Lemoff A, Zhao Z, Angulo-Barturen I, Jiménez-Díaz M.B, Wittlin S, Campbell S.F, Fidock D.A, Laleu B, Charman S.A, Ready J.M, Phillips M.A. Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria. Cell Chem Biol. 2024;31(8):1503-1517. DOI: 10.1016/j.chembiol.2024.07.001

Mambwe D, Coertzen D, Leshabane M, Mulubwa M, Njoroge M, Gibhard L, Girling G, Wicht K.J, Lee M.C.S, Wittlin S, Moreira D.R.M, Birkholtz L.M, Chibale K. hERG, Plasmodium life cycle, and cross resistance profiling of new azabenzimidazole analogues of astemizole. ACS Med Chem Lett. 2024;15(4):463-469. DOI: 10.1021/acsmedchemlett.3c00496

Nerlich C, Tiedjens F, Hertel R, Henke B, Häuer S, Panitzsch L.S, Hansen K, Franck O, Mete A, Leroy D, Schade D, Peifer C, Hannus S, Becker F, Wittlin S, Spielmann T, Beitz E. Addressing the intracellular vestibule of the plasmodial lactate transporter PfFNT by p-substituted inhibitors amplifies in vitro activity. J Med Chem. 2024;67(20):18368-18383. DOI: 10.1021/acs.jmedchem.4c01674

Nguyen W, Boulet C, Dans M.G, Loi K, Jarman K.E, Watson G.M, Tham W.H, Fairhurst K.J, Yeo T, Fidock D.A, Wittlin S, Chowdury M, de Koning-Ward T.F, Chen G, Yan D, Charman S.A, Baud D, Brand S, Jackson P.F, Cowman A.F, Gilson P.R, Sleebs B.E. Activity refinement of aryl amino acetamides that target the P. falciparum STAR-related lipid transfer 1 protein. Eur J Med Chem. 2024;270:116354. DOI: 10.1016/j.ejmech.2024.116354

Walz A, Lehmann U, Duthaler U, Mäser P, Wittlin S. In vivo antimalarial efficacy of Artemisia afra powder suspensions. Phytomedicine. 2024;129:155644. DOI: 10.1016/j.phymed.2024.155644

Walz A, Sax S, Scheurer C, Tamasi B, Mäser P, Wittlin S. Incomplete Plasmodium falciparum growth inhibition following piperaquine treatment translates into increased parasite viability in the in vitro parasite reduction ratio assay. Front Cell Infect Microbiol. 2024;14:1396786. DOI: 10.3389/fcimb.2024.1396786

Davies H, Bergmann B, Walloch P, Nerlich C, Hansen C, Wittlin S, Spielmann T, Treeck M, Beitz E. The Plasmodium lactate/H+ transporter PfFNT is essential and druggable in vivo. Antimicrob Agents Chemother. 2023;67(8):e0035623. DOI: 10.1128/aac.00356-23

Imlay L.S, Lawong A.K, Gahalawat S, Kumar A, Xing C, Mittal N, Wittlin S, Churchyard A, Niederstrasser H, Crespo-Fernandez B, Posner B.A, Gamo F.J, Baum J, Winzeler E.A, Laleu B, Ready J.M, Phillips M.A. Fast-killing tyrosine amide ((S)-SW228703) with blood- and liver-stage antimalarial activity associated with the cyclic amine resistance locus (PfCARL). ACS Infect Dis. 2023;9(3):527-539. DOI: 10.1021/acsinfecdis.2c00527

Ling D.B, Nguyen W, Looker O, Razook Z, McCann K, Barry A.E, Scheurer C, Wittlin S, Famodimu M.T, Delves M.J, Bullen H.E, Crabb B.S, Sleebs B.E, Gilson P.R. A pyridyl-furan series developed from the Open Global Health Library block red blood cell invasion and protein trafficking in Plasmodium falciparum through potential inhibition of the parasite's PI4KIIIB enzyme. ACS Infect Dis. 2023;9(9):1695-1710. DOI: 10.1021/acsinfecdis.3c00138

Mäser P, Bernhard S, Brun R, Burri C, Gagneux S, Hetzel M.W, Kaiser M, Lengeler C, Pluschke G, Reus E, Rottmann M, Utzinger J, Warryn L, Wittlin S, Keiser J. Key contributions by the Swiss Tropical and Public Health Institute towards new and better drugs for tropical diseases. Chimia (Aarau). 2023;77(9):593-606. DOI: 10.2533/chimia.2023.593

Nguyen W, Dans M.G, Currie I, Awalt J.K, Bailey B.L, Lumb C, Ngo A, Favuzza P, Palandri J, Ramesh S, Penington J, Jarman K.E, Mukherjee P, Chakraborty A, Maier A.G, van Dooren G.G, Papenfuss T, Wittlin S, Churchyard A, Baum J, Winzeler E.A, Baud D, Brand S, Jackson P.F, Cowman A.F, Sleebs B.E. 7-N-substituted-3-oxadiazole quinolones with potent antimalarial activity target the cytochrome bc1 complex. ACS Infect Dis. 2023;9(3):668-691. DOI: 10.1021/acsinfecdis.2c00607

Ren R, Wang X, Leas D.A, Scheurer C, Hövel S, Cal M, Chen G, Zhong L, Katneni K, Pham T, Patil R, Sil D, Walters M.J, Schulze T.T, Neville A.J, Dong Y, Wittlin S, Kaiser M, Davis P.H, Charman S.A, Vennerstrom J.L. Antimalarial dibenzannulated medium-ring keto lactams. ACS Infect Dis. 2023;9(10):1964-1980. DOI: 10.1021/acsinfecdis.3c00245

Walz A, Duffey M, Aljayyoussi G, Sax S, Leroy D, Besson A, Burrows J.N, Cherkaoui-Rbati M.H, Gobeau N, Westwood M-A, Siethoff C, Gamo S, Mäser P, Wittlin S. The Parasite Reduction Ratio (PRR) assay version 2: standardized assessment of Plasmodium falciparum viability after antimalarial treatment in vitro. Pharmaceuticals (Basel). 2023;16(2):163. DOI: 10.3390/ph16020163

de Vries L.E, Jansen P.A.M, Barcelo C, Munro J, Verhoef J.M.J, Pasaje C.F.A, Rubiano K, Striepen J, Abla N, Berning L, Bolscher J.M, Demarta-Gatsi C, Henderson R.W.M, Huijs T, Koolen K.M.J, Tumwebaze P.K, Yeo T, Aguiar A.C.C, Angulo-Barturen I, Churchyard A, Baum J, Fernandez B.C, Fuchs A, Gamo F.J, Guido R.V.C, Jimenez-Diaz M.B, Pereira D.B, Rochford R, Roesch C, Sanz L.M, Trevitt G, Witkowski B, Wittlin S, Cooper R.A, Rosenthal P.J, Sauerwein R.W, Schalkwijk J, Hermkens P.H.H, Bonnert R.V, Campo B, Fidock D.A, Llinas M, Niles J.C, Kooij T.W.A, Dechering K.J. Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183. Nat Commun. 2022;13:2158. DOI: 10.1038/s41467-022-29688-5

Dong Y, Sonawane Y, Maher S.P, Zeeman A.M, Chaumeau V, Vantaux A, Cooper C.A, Chiu F.C.K, Ryan E, McLaren J, Chen G, Wittlin S, Witkowski B, Nosten F, Sriraghavan K, Kyle D.E, Kocken C.H.M, Charman S.A, Vennerstrom J.L. Metabolic, pharmacokinetic, and activity profile of the liver stage antimalarial (RC-12). ACS Omega. 2022;7(14):12401-12411. DOI: 10.1021/acsomega.2c01099

Laleu B, Rubiano K, Yeo T, Hallyburton I, Anderson M, Crespo-Fernandez B, Gamo F.J, Antonova-Koch Y, Orjuela-Sanchez P, Wittlin S, Jana G.P, Maity B.C, Chenu E, Duffy J, Sjö P, Waterson D, Winzeler E, Guantai E, Fidock D.A, Hansson T. Exploring a tetrahydroquinoline antimalarial hit from the medicines for malaria pathogen box and the identification of its mode of resistance as PfeEF2. ChemMedChem. 2022;17(22):e202200393. DOI: 10.1002/cmdc.202200393

Lowe M.A, Cardenas A, Valentin J.P, Zhu Z, Abendroth J, Castro J.L, Class R, Delaunois A, Fleurance R, Gerets H, Gryshkova V, King L, Lorimer D.D, MacCoss M, Rowley J.H, Rosseels M.L, Royer L, Taylor R.D, Wong M, Zaccheo O, Chavan V.P, Ghule G.A, Tapkir B.K, Burrows J.N, Duffey M, Rottmann M, Wittlin S, Angulo-Barturen I, Jiménez-Díaz M.B, Striepen J, Fairhurst K.J, Yeo T, Fidock D.A, Cowman A.F, Favuzza P, Crespo-Fernandez B, Gamo F.J, Goldberg D.E, Soldati-Favre D, Laleu B, de Haro T. Discovery and characterization of potent, efficacious, orally available antimalarial plasmepsin X inhibitors and preclinical safety assessment of UCB7362. J Med Chem. 2022;65(20):14121-14143. DOI: 10.1021/acs.jmedchem.2c01336

Mambwe D, Korkor CM, Mabhula A, Ngqumba Z, Cloete C, Kumar M, Barros PL, Leshabane M, Coertzen D, Taylor D, Gibhard L, Njoroge M, Lawrence N, Reader J, Moreira DR, Birkholtz LM, Wittlin S, Egan TJ, Chibale K. Novel 3-trifluoromethyl-1,2,4-oxadiazole analogues of astemizole with multi-stage antiplasmodium activity and in vivo efficacy in a Plasmodium berghei mouse malaria infection model. J Med Chem. 2022;65(24):16695-16715. DOI: 10.1021/acs.jmedchem.2c01516

Xie S.C, Metcalfe R.D, Dunn E, Morton C.J, Huang S.C, Puhalovich T, Du Y, Wittlin S, Nie S, Luth M.R, Ma L, Kim M.S, Pasaje C.F.A, Kumpornsin K, Giannangelo C, Houghton F.J, Churchyard A, Famodimu M.T, Barry D.C, Gillett D.L, Dey S, Kosasih C.C, Newman W, Niles J.C, Lee M.C.S, Baum J, Ottilie S, Winzeler E.A, Creek D.J, Williamson N, Parker M.W, Brand S, Langston S.P, Dick L.R, Griffin M.D.W, Gould A.E, Tilley L. Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy. Science. 2022;376(6597):1074-1079. DOI: 10.1126/science.abn0611

Boss C, Wittlin S. Our exciting journey to ACT-451840. Chimia. 2021;75(11):916-922. DOI: 10.2533/chimia.2021.916

Cheuka P.M, Centani L, Arendse L.B, Fienberg S, Wambua L, Renga S.S, Dziwornu G.A, Kumar M, Lawrence N, Taylor D, Wittlin S, Coertzen D, Reader J, van der Watt M, Birkholtz L.M, Chibale K. New amidated 3,6-diphenylated imidazopyridazines with potent antiplasmodium activity are dual inhibitors of Plasmodium phosphatidylinositol-4-kinase and cGMP-dependent protein kinase. ACS Infect Dis. 2021;7(1):34-46. DOI: 10.1021/acsinfecdis.0c00481

Dziwornu G.A, Coertzen D, Leshabane M, Korkor C.M, Cloete C.K, Njoroge M, Gibhard L, Lawrence N, Reader J, van der Watt M, Wittlin S, Birkholtz L.M, Chibale K. Antimalarial benzimidazole derivatives incorporating phenolic mannich base side chains inhibit microtubule and hemozoin formation: structure-activity relationship and in vivo oral efficacy studies. J Med Chem. 2021;64(8):5198–5215. DOI: 10.1021/acs.jmedchem.1c00354

Hitz E, Grüninger O, Passecker A, Wyss M, Scheurer C, Wittlin S, Beck H.P, Brancucci N.M.B, Voss T.S. The catalytic subunit of Plasmodium falciparum casein kinase 2 is essential for gametocytogenesis. Commun Biol. 2021;4(1):336. DOI: 10.1038/s42003-021-01873-0

Hitz E, Wiedemar N, Passecker A, Graça B.A.S, Scheurer C, Wittlin S, Brancucci N.M.B, Vakonakis I, Mäser P, Voss T.S. The 3-phosphoinositide-dependent protein kinase 1 is an essential upstream activator of protein kinase A in malaria parasites. PLoS Biol. 2021;19(12):e3001483. DOI: 10.1371/journal.pbio.3001483

Knaab T.C, Held J, Burckhardt B.B, Rubiano K, Okombo J, Yeo T, Mok S, Uhlemann A.C, Lungerich B, Fischli C, Pessanha de Carvalho L, Mordmüller B, Wittlin S, Fidock D.A, Kurz T. 3-Hydroxy-propanamidines, a new class of orally active antimalarials targeting Plasmodium falciparum. J Med Chem. 2021;64(6):3035-3047. DOI: 10.1021/acs.jmedchem.0c01744

Laleu B, Akao Y, Ochida A, Duffy S, Lucantoni L, Shackleford D.M, Chen G, Katneni K, Chiu F.C.K, White K.L, Chen X, Sturm A, Dechering K.J, Crespo B, Sanz L.M, Wang B, Wittlin S, Charman S.A, Avery V.M, Cho N, Kamaura M. Discovery and structure-activity relationships of quinazolinone-2-carboxamide derivatives as novel orally efficacious antimalarials. J Med Chem. 2021;64(17):12582-12602. DOI: 10.1021/acs.jmedchem.1c00441

Lawong A, Gahalawat S, Okombo J, Striepen J, Yeo T, Mok S, Deni I, Bridgford J.L, Niederstrasser H, Zhou A, Posner B, Wittlin S, Gamo F.J, Crespo B, Churchyard A, Baum J, Mittal N, Winzeler E, Laleu B, Palmer M.J, Charman S.A, Fidock D.A, Ready J.M, Phillips M.A. Novel antimalarial tetrazoles and amides active against the hemoglobin degradation pathway in Plasmodium falciparum. J Med Chem. 2021;64(5):2739-2761. DOI: 10.1021/acs.jmedchem.0c02022

Le Manach C, Dam J, Woodland J.G, Kaur G, Khonde L.P, Brunschwig C, Njoroge M, Wicht K.J, Horatscheck A, Paquet T, Boyle G.A, Gibhard L, Taylor D, Lawrence N, Yeo T, Mok S, Eastman R.T, Dorjsuren D, Talley D.C, Guo H, Simeonov A, Reader J, van der Watt M, Erlank E, Venter N, Zawada J.W, Aswat A, Nardini L, Coetzer T.L, Lauterbach S.B, Bezuidenhout B.C, Theron A, Mancama D, Koekemoer L.L, Birkholtz L.M, Wittlin S, Delves M, Ottilie S, Winzeler E.A, von Geldern T.W, Smith D, Fidock D.A, Street L.J, Basarab G.S, Duffy J, Chibale K. Identification and profiling of a novel diazaspiro[3.4]octane chemical series active against multiple stages of the human malaria parasite Plasmodium falciparum and optimization efforts. J Med Chem. 2021;64(4):2291-2309. DOI: 10.1021/acs.jmedchem.1c00034

Leas D.A, Sanford A.G, Wu J, Cal M, Kaiser M, Wittlin S, Hemsley R.M, Darner E.B, Lui L.M, Davis P.H, Vennerstrom J.L. Diaryl ureas as an antiprotozoal chemotype. ACS Infect Dis. 2021;7(6):1578-1583. DOI: 10.1021/acsinfecdis.1c00135

Murithi J.M, Pascal C, Bath J, Boulenc X, Gnadig N.F, Pasaje C.F.A, Rubiano K, Yeo T, Mok S, Klieber S, Desert P, Jimenez-Diaz M.B, Marfurt J, Rouillier M, Cherkaoui-Rbati M.H, Gobeau N, Wittlin S, Uhlemann A.C, Price R.N, Wirjanata G, Noviyanti R, Tumwebaze P, Cooper R.A, Rosenthal P.J, Sanz L.M, Gamo F.J, Joseph J, Singh S, Bashyam S, Augereau J.M, Giraud E, Bozec T, Vermat T, Tuffal G, Guillon J.M, Menegotto J, Salle L, Louit G, Cabanis M.J, Nicolas M.F, Doubovetzky M, Merino R, Bessila N, Angulo-Barturen I, Baud D, Bebrevska L, Escudie F, Niles J.C, Blasco B, Campbell S, Courtemanche G, Fraisse L, Pellet A, Fidock D.A, Leroy D. The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance. Sci Transl Med. 2021;13(603):eabg6013. DOI: 10.1126/scitranslmed.abg6013

Okaniwa M, Shibata A, Ochida A, Akao Y, White K.L, Shackleford D.M, Duffy S, Lucantoni L, Dey S, Striepen J, Yeo T, Mok S, Aguiar A.C.C, Sturm A, Crespo B, Sanz L.M, Churchyard A, Baum J, Pereira D.B, Guido R.V.C, Dechering K.J, Wittlin S, Uhlemann A.C, Fidock D.A, Niles J.C, Avery V.M, Charman S.A, Laleu B. Repositioning and characterization of 1-(pyridin-4-yl)pyrrolidin-2-one derivatives as Plasmodium cytoplasmic prolyl-trna synthetase inhibitors. ACS Infect Dis. 2021;7(6):1680-1689. DOI: 10.1021/acsinfecdis.1c00020

Palmer M.J, Deng X, Watts S, Krilov G, Gerasyuto A, Kokkonda S, El Mazouni F, White J, White K.L, Striepen J, Bath J, Schindler K.A, Yeo T, Shackleford D.M, Mok S, Deni I, Lawong A, Huang A, Chen G, Wang W, Jayaseelan J, Katneni K, Patil R, Saunders J, Shahi S.P, Chittimalla R, Angulo-Barturen I, Jimenez-Diaz M.B, Wittlin S, Tumwebaze P.K, Rosenthal P.J, Cooper R.A, Aguiar A.C.C, Guido R.V.C, Pereira D.B, Mittal N, Winzeler E.A, Tomchick D.R, Laleu B, Burrows J.N, Rathod P.K, Fidock D.A, Charman S.A, Phillips M.A. Potent antimalarials with development potential identified by structure-guided computational optimization of a pyrrole-based dihydroorotate dehydrogenase inhibitor series. J Med Chem. 2021;64(9):6085-6136. DOI: 10.1021/acs.jmedchem.1c00173

Shackleford D.M, Chiu F.C.K, Katneni K, Blundell S, McLaren J, Wang X, Zhou L, Sriraghavan K, Alker A.M, Hunziker D, Scheurer C, Zhao Q, Dong Y, Mohrle J.J, Abla N, Matile H, Wittlin S, Vennerstrom J.L, Charman S.A. Cytochrome P450-mediated metabolism and CYP Inhibition for the synthetic peroxide antimalarial OZ439. ACS Infect Dis. 2021;7(7):1885-1893. DOI: 10.1021/acsinfecdis.1c00225

Wittlin S, Mäser P. From magic bullet to magic bomb: reductive bioactivation of antiparasitic agents. ACS Infect Dis. 2021;7(10):2777-2786. DOI: 10.1021/acsinfecdis.1c00118

Xie S.C, Metcalfe R.D, Mizutani H, Puhalovich T, Hanssen E, Morton C.J, Du Y, Dogovski C, Huang S.C, Ciavarri J, Hales P, Griffin R.J, Cohen L.H, Chuang B.C, Wittlin S, Deni I, Yeo T, Ward K.E, Barry D.C, Liu B, Gillett D.L, Crespo-Fernandez B.F, Ottilie S, Mittal N, Churchyard A, Ferguson D, Aguiar A.C.C, Guido R.V.C, Baum J, Hanson K.K, Winzeler E.A, Gamo F.J, Fidock D.A, Baud D, Parker M.W, Brand S, Dick L.R, Griffin M.D.W, Gould A.E, Tilley L. Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome. Proc Natl Acad Sci U S A. 2021;118(39):e2107213118. DOI: 10.1073/pnas.2107213118

Ahenkorah S, Coertzen D, Tong J.X, Fridianto K, Wittlin S, Birkholtz L.M, Tan K.S.W, Lam Y, Go M.L, Haynes R.K. Antimalarial N1,N3-dialkyldioxonaphthoimidazoliums: synthesis, biological activity, and structure-activity relationships. ACS Med Chem Lett. 2020;11:49-55. DOI: 10.1021/acsmedchemlett.9b00457

Burgert L, Rottmann M, Wittlin S, Gobeau N, Krause A, Dingemanse J, Möhrle J.J, Penny M.A. Ensemble modeling highlights importance of understanding parasite-host behavior in preclinical antimalarial drug development. Sci Rep. 2020;10:4410. DOI: 10.1038/s41598-020-61304-8

Horatscheck A, Andrijevic A, Nchinda A.T, Le Manach C, Paquet T, Khonde L.P, Dam J, Pawar K, Taylor D, Lawrence N, Brunschwig C, Gibhard L, Njoroge M, Reader J, van der Watt M, Wicht K, de Sousa A.C.C, Okombo J, Maepa K, Egan T.J, Birkholtz L.M, Basarab G.S, Wittlin S, Fish P.V, Street L.J, Duffy J, Chibale K. Identification of 2,4-disubstituted imidazopyridines as hemozoin formation inhibitors with fast-killing kinetics and in vivo efficacy in the Plasmodium falciparum NSG mouse model. J Med Chem. 2020;63(21):13013-13030. DOI: 10.1021/acs.jmedchem.0c01411

Kokkonda S, Deng X, White K.L, El Mazouni F, White J, Shackleford D.M, Katneni K, Chiu F.C.K, Barker H, McLaren J, Crighton E, Chen G, Angulo-Barturen I, Jimenez-Diaz M.B, Ferrer S, Huertas-Valentin L, Martinez-Martinez M.S, Lafuente-Monasterio M.J, Chittimalla R, Shahi S.P, Wittlin S, Waterson D, Burrows J.N, Matthews D, Tomchick D, Rathod P.K, Palmer M.J, Charman S.A, Phillips M.A. Lead optimization of a pyrrole-based dihydroorotate dehydrogenase inhibitor series for the treatment of malaria. J Med Chem. 2020;63(9):4929-4956. DOI: 10.1021/acs.jmedchem.0c00311

Potluri V, Shandil R.K, Gavara R, Sambasivam G, Campo B, Wittlin S, Narayanan S. Discovery of FNDR-20123, a histone deacetylase inhibitor for the treatment of Plasmodium falciparum malaria. Malar J. 2020;19:365. DOI: 10.1186/s12936-020-03421-3

Attram H.D, Wittlin S, Chibale K. Incorporation of an intramolecular hydrogen bonding motif in the side chain of antimalarial benzimidazoles. MedChemComm. 2019;10(3):450-455. DOI: 10.1039/c8md00608c

Baartzes N, Stringer T, Seldon R, Warner D.F, Taylor D, Wittlin S, Chibale K, Smith G.S. Bioisosteric ferrocenyl aminoquinoline-benzimidazole hybrids: antimicrobial evaluation and mechanistic insights. Eur J Med Chem. 2019;180:121-133. DOI: 10.1016/j.ejmech.2019.06.069

Baragaña B, Forte B, Choi R, Nakazawa Hewitt S, Bueren-Calabuig J.A, Pisco J.P, Peet C, Dranow D.M, Robinson D.A, Jansen C, Norcross N.R, Vinayak S, Anderson M, Brooks C.F, Cooper C.A, Damerow S, Delves M, Dowers K, Duffy J, Edwards T.E, Hallyburton I, Horst B.G, Hulverson M.A, Ferguson L, Jiménez-Díaz M.B, Jumani R.S, Lorimer D.D, Love M.S, Maher S, Matthews H, McNamara C.W, Miller P, O'Neill S, Ojo K.K, Osuna-Cabello M, Pinto E, Post J, Riley J, Rottmann M, Sanz L.M, Scullion P, Sharma A, Shepherd S.M, Shishikura Y, Simeons F.R.C, Stebbins E.E, Stojanovski L, Straschil U, Tamaki F.K, Tamjar J, Torrie L.S, Vantaux A, Witkowski B, Wittlin S, Yogavel M, Zuccotto F, Angulo-Barturen I, Sinden R, Baum J, Gamo F.J, Mäser P, Kyle D.E, Winzeler E.A, Myler P.J, Wyatt P.G, Floyd D, Matthews D, Sharma A, Striepen B, Huston C.D, Gray D.W, Fairlamb A.H, Pisliakov A.V, Walpole C, Read K.D, Van Voorhis W.C, Gilbert I.H. Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis. Proc Natl Acad Sci USA. 2019;116(14):7015-7020. DOI: 10.1073/pnas.1814685116

Gilson P.R, Nguyen W, Poole W.A, Teixeira J.E, Thompson J.K, Guo K, Stewart R.J, Ashton T.D, White K.L, Sanz L.M, Gamo F.J, Charman S.A, Wittlin S, Duffy J, Tonkin C.J, Tham W.H, Crabb B.S, Cooke B.M, Huston C.D, Cowman A.F, Sleebs B.E. Evaluation of 4-amino 2-anilinoquinazolines against Plasmodium and other apicomplexan parasites in vitro and in a P. falciparum humanized NOD-scid IL2Rynull mouse model of malaria. Antimicrob Agents Chemother. 2019;63(3):e01804-18. DOI: 10.1128/AAC.01804-18

Hooft van Huijsduijnen R, Wells T, Tanner M, Wittlin S. Two successful decades of Swiss collaborations to develop new anti-malarials. Malar J. 2019;18:94. DOI: 10.1186/s12936-019-2728-8

Jourdan J, Walz A, Matile H, Schmidt A, Wu J, Wang X, Dong Y, Vennerstrom J.L, Schmidt R.S, Wittlin S, Mäser P. Stochastic protein alkylation by antimalarial peroxides. ACS Infect Dis. 2019;5(12):2067-2075. DOI: 10.1021/acsinfecdis.9b00264

Krieg R, Jortzik E, Goetz A.A, Blandin S, Wittlin S, Elhabiri M, Rahbari M, Nuryyeva S, Voigt K, Dahse H.M, Brakhage A, Beckmann S, Quack T, Grevelding C.G, Pinkerton A.B, Schonecker B, Burrows J, Davioud-Charvet E, Rahlfs S, Becker K. Author correction: Arylmethylamino steroids as antiparasitic agents. Nat Commun. 2019;10:2997. DOI: 10.1038/s41467-019-11018-x

Kumar M, Okombo J, Mambwe D, Taylor D, Lawrence N, Reader J, Watt M.V, Fontinha D, Sanches-Vaz M, Bezuidenhout B.C, Lauterbach S, Liebenberg D, Birkholtz L.M, Coetzer T.L, Prudencio M, Egan T.J, Wittlin S, Chibale K. Multistage antiplasmodium activity of astemizole analogues and inhibition of hemozoin formation as a contributor to their mode of action. ACS Infect Dis. 2019;5(2):303-315. DOI: 10.1021/acsinfecdis.8b00272

Mayoka G, Njoroge M, Gibhard L, Sanches-VazM, Fontinha D, Birkholtz L.M, Reader J, Van der Watt M, Coetzer T.L, Lauterbach S, Churchyard A, Bezuidenhout B, Egan T.J, Yeates C, Wittlin S, Prudêncio M, Chibale K. Structure–activity relationship studies and Plasmodium life cycle profiling identifies pan-active N-aryl-3-trifluoromethyl pyrido[1,2-a]benzimidazoles which are efficacious in an in vivo mouse model of malaria. J Med Chem. 2019;62(2):1022-1035. DOI: 10.1021/acs.jmedchem.8b01769

Okombo J, Brunschwig C, Singh K, Dziwornu G.A, Barnard L, Njoroge M, Wittlin S, Chibale K. Antimalarial pyrido[1,2-a]benzimidazole derivatives with mannich base side chains: synthesis, pharmacological evaluation and reactive metabolite trapping studies. ACS Infect Dis. 2019;5(3):372-384. DOI: 10.1021/acsinfecdis.8b00279

Schalkwijk J, Allman E.L, Jansen P.A.M, de Vries L.E, Verhoef J.M.J, Jackowski S, Botman P.N.M, Beuckens-Schortinghuis C.A, Koolen K.M.J, Bolscher J.M, Vos M.W, Miller K, Reeves S.A, Pett H, Trevitt G, Wittlin S, Scheurer C, Sax S, Fischli C, Angulo-Barturen I, Jimenez-Diaz M.B, Josling G, Kooij T.W.A, Bonnert R, Campo B, Blaauw R.H, Rutjes Fpjt, Sauerwein R.W, Llinas M, Hermkens P.H.H, Dechering K.J. Antimalarial pantothenamide metabolites target acetyl-coenzyme A biosynthesis in Plasmodium falciparum. Sci Transl Med. 2019;11(510):eaas9917. DOI: 10.1126/scitranslmed.aas9917

Walz A, Leroy D, Andenmatten N, Mäser P, Wittlin S. Anti-malarial ozonides OZ439 and OZ609 tested at clinically relevant compound exposure parameters in a novel ring-stage survival assay. Malar J. 2019;18:427. DOI: 10.1186/s12936-019-3056-8

Boss C, Wittlin S. Recent trends in malaria research. In: Bronson J, ed. 2018 Medicinal chemistry reviews: from the medicinal chemistry division of the ACS. 53, 293-311. Minneapolis: Division of Medicinal Chemistry, 2018

Brunschwig C, Lawrence N, Taylor D, Abay E, Njoroge M, Basarab G.S, Le Manach C, Paquet T, Gonzalez Cabrera D, Nchinda A.T, de Kock C, Wiesner L, Denti P, Waterson D, Blasco B, Leroy D, Witty M.J, Donini C, Duffy J, Wittlin S, White K.L, Charman S.A, Jimenez-Diaz M.B, Angulo-Barturen I, Herreros E, Gamo F.J, Rochford R, Mancama D, Coetzer T.L, van der Watt M.E, Reader J, Birkholtz L.M, Marsh K.C, Solapure S.M, Burke J.E, McPhail J.A, Vanaerschot M, Fidock D.A, Fish P.V, Siegl P, Smith D.A, Wirjanata G, Noviyanti R, Price R.N, Marfurt J, Silue K.D, Street L.J, Chibale K. Erratum for Brunschwig et al., "UCT943, a next-generation Plasmodium falciparum PI4K Inhibitor rreclinical candidate for the treatment of malaria". Antimicrob Agents Chemother. 2018;62(11):e01941-18. DOI: 10.1128/AAC.01941-18

Brunschwig C, Lawrence N, Taylor D, Abay E, Njoroge M, Basarab G.S, Le Manach C, Paquet T, Gonzàlez Cabrera D, Nchinda A.T, de Kock C, Wiesner L, Denti P, Waterson D, Blasco B, Leroy D, Witty M.J, Donini C, Duffy J, Wittlin S, White K.L, Charman S.A, Jimenez-Diaz M.B, Angulo-Barturen I, Herreros E, Gamo F.J, Rochford R, Mancama D, Coetzer T.L, Van der Watt M.E, Reader J, Birkholtz L.M, Marsh K.C, Solapure S.M, Vanaerschot M, Fidock D.A, Fish P.V, Siegl P, Smith D.A, Wirjanata G, Noviyanti R, Price R.N, Marfurt J, Silue K.D, Street L.J, Chibale K. UCT943, a next generation Plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of malaria. Antimicrob Agents Chemother. 2018;62(9):e00012-18. DOI: 10.1128/AAC.00012-18

Cheuka P.M, Lawrence N, Taylor D, Wittlin S, Chibale K. Antiplasmodial imidazopyridazines: structure-activity relationship studies lead to the identification of analogues with improved solubility and hERG profiles. MedChemComm. 2018;9(10):1733-1745. DOI: 10.1039/C8MD00382C

Gibhard L, Njoroge M, Paquet T, Brunschwig C, Taylor D, Lawrence N, Abay E, Wittlin S, Wiesner L, Street L.J, Chibale K, Basarab G.S. Investigating sulfoxide-to-sulfone conversion as a prodrug strategy for a phosphatidylinositol 4-kinas inhibitor in a humanized mouse model of malaria. Antimicrob Agents Chemother. 2018;62(12):e00261-18. DOI: 10.1128/AAC.00261-18

Grogg M, Hilvert D, Ebert M.O, Beck A.K, Seebach D, Kurth F, Dittrich P.S, Sparr C, Wittlin S, Rottmann M, Mäser P. Cell penetration, herbicidal activity, and in-vivo-toxicity of oligo-arginine derivatives and of novel guanidinium-rich compounds derived from the biopolymer cyanophycin. Helvetica Chimica Acta. 2018;101(10):e1800112. DOI: 10.1002/hlca.201800112

Kaur G, Pavadai E, Wittlin S, Chibale K. 3D-QSAR modeling and synthesis of new fusidic acid derivatives as antiplasmodial agents. J Chem Inf Model. 2018;58(8):1553-1560. DOI: 10.1021/acs.jcim.8b00105

Le Manach C, Paquet T, Wicht K, Nchinda A.T, Brunschwig C, Njoroge M, Gibhard L, Taylor D, Lawrence N, Wittlin S, Eyermann C.J, Basarab G.S, Duffy J, Fish P.V, Street L.J, Chibale K. Antimalarial lead-optimization studies on a 2,6-imidazopyridine series within a constrained chemical space to circumvent atypical dose-response curves against multidrug resistant parasite strains. J Med Chem. 2018;61(20):9371-9385. DOI: 10.1021/acs.jmedchem.8b01333

Nchinda A.T, Le Manach C, Paquet T, Gonzalez Cabrera D, Wicht K.J, Brunschwig C, Njoroge M, Abay E, Taylor D, Lawrence N, Wittlin S, Jimenez-Diaz M.B, Santos Martinez M, Ferrer S, Angulo-Barturen I, Lafuente-Monasterio M.J, Duffy J, Burrows J, Street L.J, Chibale K. Identification of fast-acting 2,6-disubstituted imidazopyridines that are efficacious in the In Vivo humanized Plasmodium falciparum NODscidIL2Rγnull mouse model of malaria. J Med Chem. 2018;61(9):4213-4227. DOI: 10.1021/acs.jmedchem.8b00382

Abla N, Bashyam S, Charman S.A, Greco B, Hewitt P, Jimenez-Diaz M.B, Katneni K, Kubas H, Picard D, Sambandan Y, Sanz L, Smith D, Wang T, Willis P, Wittlin S, Spangenberg T. Long-lasting and fast-acting in vivo efficacious antiplasmodial azepanylcarbazole amino alcohol. ACS Med Chem Lett. 2017;8(12):1304-1308. DOI: 10.1021/acsmedchemlett.7b00391

Baumgärtner F, Jourdan J, Scheurer C, Blasco B, Campo B, Mäser P, Wittlin S. In vitro activity of anti-malarial ozonides against an artemisinin-resistant isolate. Malar J. 2017;16:45. DOI: 10.1186/s12936-017-1696-0

Dong Y, Wang X, Kamaraj S, Bulbule V.J, Chiu F.C, Chollet J, Dhanasekaran M, Hein C.D, Papastogiannidis P, Morizzi J, Shackleford D.M, Barker H, Ryan E, Scheurer C, Tang Y, Zhao Q, Zhou L, White K.L, Urwyler H, Charman W.N, Matile H, Wittlin S, Charman S.A, Vennerstrom J.L. Structure-activity relationship of the antimalarial ozonide artefenomel (OZ439). J Med Chem. 2017;60(7):2654-2668. DOI: 10.1021/acs.jmedchem.6b01586

Espinoza-Moraga M, Singh K, Njoroge M, Kaur G, Okombo J, De Kock C, Smith P.J, Wittlin S, Chibale K. Synthesis and biological characterisation of ester and amide derivatives of fusidic acid as antiplasmodial agents. Bioorg Med Chem Lett. 2017;27(3):658-661. DOI: 10.1016/j.bmcl.2016.11.077

Krieg R, Jortzik E, Goetz A.A, Blandin S, Wittlin S, Elhabiri M, Rahbari M, Nuryyeva S, Voigt K, Dahse H.M, Brakhage A, Beckmann S, Quack T, Grevelding C.G, Pinkerton A.B, Schonecker B, Burrows J, Davioud-Charvet E, Rahlfs S, Becker K. Arylmethylamino steroids as antiparasitic agents. Nat Commun. 2017;8:14478. DOI: 10.1038/ncomms14478

Leven M, Knaab T.C, Held J, Duffy S, Meister S, Fischli C, Meitzner D, Lehmann U, Lungerich B, Kuna K, Stahlke P, Delves M.J, Buchholz M, Winzeler E.A, Avery V.M, Mordmuller B, Wittlin S, Kurz T. 3-hydroxy-N'-arylidenepropanehydrazonamides with halo-substituted phenanthrene scaffolds cure P. berghei infected mice when administered perorally. J Med Chem. 2017;60(14):6036-6044. DOI: 10.1021/acs.jmedchem.7b00140

Paquet T, Le Manach C, Cabrera D.G, Younis Y, Henrich P.P, Abraham T.S, Lee M.C.S, Basak R, Ghidelli-Disse S, Lafuente-Monasterio M.J, Bantscheff M, Ruecker A, Blagborough A.M, Zakutansky S.E, Zeeman A.M, White K.L, Shackleford D.M, Mannila J, Morizzi J, Scheurer C, Angulo-Barturen I, Martinez M.S, Ferrer S, Sanz L.M, Gamo F.J, Reader J, Botha M, Dechering K.J, Sauerwein R.W, Tungtaeng A, Vanachayangkul P, Lim C.S, Burrows J, Witty M.J, Marsh K.C, Bodenreider C, Rochford R, Solapure S.M, Jimenez-Diaz M.B, Wittlin S, Charman S.A, Donini C, Campo B, Birkholtz L.M, Hanson K.K, Drewes G, Kocken C.H.M, Delves M.J, Leroy D, Fidock D.A, Waterson D, Street L.J, Chibale K. Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase. Sci Transl Med. 2017;9(387):eaad9735. DOI: 10.1126/scitranslmed.aad9735

Pavadai E, Kaur G, Wittlin S, Chibale K. Identification of steroid-like natural products as antiplasmodial agents by 2D and 3D similarity-based virtual screening. MedChemComm. 2017;8(6):1152-1157. DOI: 10.1039/c7md00063d

Singh K, Okombo J, Brunschwig C, Ndubi F, Barnard L, Wilkinson C, Njogu P.M, Njoroge M, Laing L, Machado M, Prudencio M, Reader J, Botha M, Nondaba S, Birkholtz L.M, Lauterbach S, Churchyard A, Coetzer T.L, Burrows J.N, Yeates C, Denti P, Wiesner L, Egan T.J, Wittlin S, Chibale K. Antimalarial pyrido[1,2-a]benzimidazoles: lead optimization, parasite life cycle stage profile, mechanistic evaluation, killing kinetics, and in vivo oral efficacy in a mouse model. J Med Chem. 2017;60(4):1432-1448. DOI: 10.1021/acs.jmedchem.6b01641

Wu Y, Xu Z.J, Wittlin S. Probing the peroxycarbenium [3+2] cycloaddition reactions with 1,2-disubstituted ethylenes: results and insights. Chemistry. 2017;23(9):2031-2034. DOI: 10.1002/chem.201605871

Baragaña B, Norcross N.R, Wilson C, Porzelle A, Hallyburton I, Grimaldi R, Osuna-Cabello M, Norval S, Riley J, Stojanovski L, Simeons F.R, Wyatt P.G, Delves M.J, Meister S, Duffy S, Avery V.M, Winzeler E.A, Sinden R.E, Wittlin S, Frearson J.A, Gray D.W, Fairlamb A.H, Waterson D, Campbell S.F, Willis P, Read K.D, Gilbert I.H. Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy. J Med Chem. 2016;59(21):9672-9685. DOI: 10.1021/acs.jmedchem.6b00723

Boss C, Aissaoui H, Amaral N, Bauer A, Bazire S, Binkert C, Brun R, Burki C, Ciana C.L, Corminboeuf O, Delahaye S, Dollinger C, Fischli C, Fischli W, Flock A, Frantz M.C, Girault M, Grisostomi C, Friedli A, Heidmann B, Hinder C, Jacob G, Le Bihan A, Malrieu S, Mamzed S, Merot A, Meyer S, Peixoto S, Petit N, Siegrist R, Trollux J, Weller T, Wittlin S. Discovery and characterization of ACT-451840: an antimalarial drug with a novel mechanism of action. ChemMedChem. 2016;11(18):1995-2014. DOI: 10.1002/cmdc.201600298

Jortzik E, Zocher K, Isernhagen A, Mailu B.M, Rahlfs S, Viola G, Wittlin S, Hunt N.H, Ihmels H, Becker K. Benzo[b]quinolizinium derivatives have a strong antimalarial activity and inhibit indoleamine dioxygenase. Antimicrob Agents Chemother. 2016;60(1):115-125. DOI: 10.1128/AAC.01066-15