References
- Neglected tropical diseases [Internet]. Geneva: World Health Organization; [ cited 2023]. Available from: www.who.int/health-topics/neglected-tropical-diseases
- Working to overcome the global impact of neglected tropical diseases: First WHO report on neglected tropical diseases. Geneva: World Health Organization; 2010. Licence: CC BY-NC-SA 3.0 IGO.
- Global report on neglected tropical diseases 2023. Geneva: World Health Organization; 2023. Licence: CC BY-NC-SA 3.0 IGO.
- Ending the neglect to attain the Sustainable Development Goals: a road map for neglected tropical diseases 2021–2030. Geneva: World Health Organization; 2020. Licence: CC BY-NC-SA 3.0 IGO.
- Varikuti S, Jha BK, Volpedo G, et al. Host-directed drug therapies for neglected tropical diseases caused by protozoan parasites. Front Microbiol. 2018;9:2655. doi:10.3389/fmicb.2018.02655
- Jensen HB, Ravnborg M, Dalgas U, et al. 4-Aminopyridine for symptomatic treatment of multiple sclerosis: a systematic review. Ther Adv Neurol Disord. 2014;7(2):97–113. doi:10.1177/1756285613512712
- Lipinski CA, Lombardo F, Dominy BW, et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews. 1997;23(1-3):3–25. doi:10.1016/S0169-409X(96)00423-1
- Congreve M, Carr R, Murray C, et al. A ‘Rule of Three’ for fragment-based lead discovery? Drug Discov Today. 2003;8(19):876–877. doi:10.1016/S1359-6446(03)02831-9
- O'Donovan DH, De Fusco C, Kuhnke L, et al. Trends in molecular properties, bioavailability, and permeability across the bayer compound collection: miniperspective. J Med Chem. 2023;66(4):2347–2360. doi:10.1021/acs.jmedchem.2c01577
- Veber DF, Johnson SR, Cheng H-Y, et al. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem. 2002;45(12):2615–2623. doi:10.1021/jm020017n
- DeGoey DA, Chen H-J, Cox PB, et al. Beyond the rule of 5: lessons learned from AbbVie's drugs and compound collection. J Med Chem. 2018;61(7):2636–2651. doi:10.1021/acs.jmedchem.7b00717
- Hitchcock SA, Pennington LD. Structure−brain exposure relationships. J Med Chem. 2006;49(26):7559–7583. doi:10.1021/jm060642i
- Research & development portfolio [Internet]. Geneva: Drugs for Neglected Diseases initiative; [ cited 2023 Aug 23]. Available from: https://dndi.org/research-development/portfolio/
- Šink R, Sosič I, Živec M, et al. Design, synthesis, and evaluation of new thiadiazole-based direct inhibitors of Enoyl Acyl carrier protein reductase (InhA) for the treatment of tuberculosis. J Med Chem. 2015;58(2):613–624. doi:10.1021/jm501029r
- Azzali E, Machado D, Kaushik A, et al. Substituted N -phenyl-5-(2-(phenylamino)thiazol-4-yl)isoxazole-3-carboxamides are valuable antitubercular candidates that evade innate efflux machinery. J Med Chem. 2017;60(16):7108–7122. doi:10.1021/acs.jmedchem.7b00793
- Girardini M, Ferlenghi F, Annunziato G, et al. Expanding the knowledge around antitubercular 5-(2-aminothiazol-4-yl)isoxazole-3-carboxamides: hit–to–lead optimization and release of a novel antitubercular chemotype via scaffold derivatization. Eur J Med Chem. 2023;245:114916. doi:10.1016/j.ejmech.2022.114916
- Murithi JM, Pascal C, Bath J, et al. 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
- Hameed PS, Solapure S, Patil V, et al. Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate. Nat Commun. 2015;6(1):6715. doi:10.1038/ncomms7715
- Parthasarathy A, Kalesh K. Defeating the trypanosomatid trio: proteomics of the protozoan parasites causing neglected tropical diseases. RSC Med Chem. 2020;11(6):625–645. doi:10.1039/D0MD00122H
- Chagas disease (also known as American trypanosomiasis) [Internet]. Geneva: World Health Organization; [ cited 2023 Aug 24]. Available from: www.who.int/en/news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis)
- Pérez-Molina JA, Molina I. Chagas disease. The Lancet. 2018;391(10115):82–94. doi:10.1016/S0140-6736(17)31612-4
- Bern C, Montgomery SP, Herwaldt BL, et al. Evaluation and treatment of chagas disease in the United States: a systematic review. JAMA. 2007;298(18):2171. doi:10.1001/jama.298.18.2171
- Choi JY, Calvet CM, Gunatilleke SS, et al. Rational development of 4-aminopyridyl-based inhibitors targeting Trypanosoma cruzi CYP51 as anti-chagas agents. J Med Chem. 2013;56(19):7651–7668. doi:10.1021/jm401067s
- Podust LM, Von Kries JP, Eddine AN, et al. Small-molecule scaffolds for CYP51 inhibitors identified by high-throughput screening and defined by x-ray crystallography. Antimicrob Agents Chemother. 2007;51(11):3915–3923. doi:10.1128/AAC.00311-07
- Chen C-K, Doyle PS, Yermalitskaya LV, et al. Trypanosoma cruzi CYP51 inhibitor derived from a Mycobacterium tuberculosis screen hit. PLOS Negl Trop Dis. 2009;3(2):e372. doi:10.1371/journal.pntd.0000372
- Choi JY, Calvet CM, Vieira DF, et al. R -configuration of 4-aminopyridyl-based inhibitors of CYP51 confers superior efficacy against Trypanosoma cruzi. ACS Med Chem Lett. 2014;5(4):434–439. doi:10.1021/ml500010m
- Calvet CM, Vieira DF, Choi JY, et al. 4-aminopyridyl-based CYP51 inhibitors as anti- trypanosoma cruzi drug leads with improved pharmacokinetic profile and in vivo potency. J Med Chem. 2014;57(16):6989–7005. doi:10.1021/jm500448u
- Vieira DF, Choi JY, Calvet CM, et al. Binding mode and potency of N -indolyloxopyridinyl-4-aminopropanyl-based inhibitors targeting Trypanosoma cruzi CYP51. J Med Chem. 2014;57(23):10162–10175. doi:10.1021/jm501568b
- Calvet CM, Choi JY, Thomas D, et al. 4-aminopyridyl-based lead compounds targeting CYP51 prevent spontaneous parasite relapse in a chronic model and improve cardiac pathology in an acute model of Trypanosoma cruzi infection. PLoS Negl Trop Dis. 2017;11(12):e0006132. doi:10.1371/journal.pntd.0006132
- Keenan M, Chaplin JH, Alexander PW, et al. Two analogues of fenarimol show curative activity in an experimental model of chagas disease. J Med Chem. 2013;56(24):10158–10170. doi:10.1021/jm401610c
- Keenan M, Abbott MJ, Alexander PW, et al. Analogues of fenarimol are potent inhibitors of Trypanosoma cruzi and are efficacious in a murine model of Chagas disease. J Med Chem. 2012;55(9):4189–4204. doi:10.1021/jm401610c
- Friggeri L, Scipione L, Costi R, et al. New promising compounds with in vitro nanomolar activity against Trypanosoma cruzi. ACS Med Chem Lett. 2013;4(6):538–541. doi:10.1021/ml400039r
- Molina I, Gómez I, Prat J, et al. Randomized trial of posaconazole and benznidazole for chronic Chagas' disease. N Engl J Med. 2014;370(20):1899–1908. doi:10.1056/NEJMoa1313122
- Torrico F, Gascon J, Ortiz L, et al. Treatment of adult chronic indeterminate Chagas disease with benznidazole and three E1224 dosing regimens: a proof-of-concept, randomised, placebo-controlled trial. Lancet Infect Dis. 2018;18(4):419–430. doi:10.1016/S1473-3099(17)30538-8
- De Rycker M, Wyllie S, Horn D, et al. Anti-trypanosomatid drug discovery: progress and challenges. Nat Rev Microbiol. 2023;21(1):35–50. doi:10.1038/s41579-022-00777-y
- Brand S, Ko EJ, Viayna E, et al. Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi. J Med Chem. 2017;60(17):7284–7299. doi:10.1021/acs.jmedchem.7b00463
- McGonagle K, Tarver GJ, Cantizani J, et al. Identification and development of a series of disubstituted piperazines for the treatment of Chagas disease. Eur J Med Chem. 2022;238:114421. doi:10.1016/j.ejmech.2022.114421
- Büscher P, Cecchi G, Jamonneau V, et al. Human African trypanosomiasis. The Lancet. 2017;390(10110):2397–2409. doi:10.1016/S0140-6736(17)31510-6
- WHO interim guidelines for the treatment of gambiense human African trypanosomiasis. Geneva: World Health Organization; 2019. Licence: CC BY-NC-SA 3.0 IGO.
- Control and surveillance of human African trypanosomiasis: report of a WHO expert committee. Geneva: World Health Organization; 2013. Licence: CC BY-NC-SA 3.0 IGO.
- Mesu VKBK, Kalonji WM, Bardonneau C, et al. Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: a pivotal multicentre, randomised, non-inferiority trial. The Lancet. 2018;391(10116):144–154. doi:10.1016/S0140-6736(17)32758-7
- EMA gives positive opinion to Fexinidazole Winthrop as first oral treatment of acute form of sleeping sickness (rhodesiense) found in East and Southern Africa [Internet]. Geneva: Drugs for Neglected diseases; [ cited 2024 Jan 24]. Available from: https://dndi.org/press-releases/2023/ema-gives-positive-opinion-fexinidazole-winthrop-first-oral-treatment-sleeping-sickness-rhodesiense/
- Betu Kumeso VK, Kalonji WM, Rembry S, et al. Efficacy and safety of acoziborole in patients with human African trypanosomiasis caused by Trypanosoma brucei gambiense: a multicentre, open-label, single-arm, phase 2/3 trial. Lancet Infect Dis. 2022;S1473309922006600. doi:10.1016/S1473-3099(22)00660-0
- Patel G, Karver CE, Behera R, et al. Kinase scaffold repurposing for neglected disease drug discovery: discovery of an efficacious, lapatanib-derived lead compound for trypanosomiasis. J Med Chem. 2013;56(10):3820–3832. doi:10.1021/jm400349k
- Devine W, Woodring JL, Swaminathan U, et al. Protozoan parasite growth inhibitors discovered by cross-screening yield potent scaffolds for lead discovery. J Med Chem. 2015;58(14):5522–5537. doi:10.1021/acs.jmedchem.5b00515
- Devine W, Thomas SM, Erath J, et al. Antiparasitic lead discovery: toward optimization of a chemotype with activity against multiple protozoan parasites. ACS Med Chem Lett. 2017;8(3):350–354. doi:10.1021/acsmedchemlett.7b00011
- Woodring JL, Bachovchin KA, Brady KG, et al. Optimization of physicochemical properties for 4-anilinoquinazoline inhibitors of trypanosome proliferation. European Journal of Medicinal Chemistry. 2017;141:446–459. doi:10.1016/j.ejmech.2017.10.007
- Ferrins L, Sharma A, Thomas SM, et al. Anilinoquinoline based inhibitors of trypanosomatid proliferation. PLOS Negl Trop Dis. 2018;12(11):e0006834. doi:10.1371/journal.pntd.0006834
- Veale CGL, Hoppe HC. Screening of the Pathogen Box reveals new starting points for anti-trypanosomal drug discovery. Med Chem Commun. 2018;9(12):2037–2044. doi:10.1039/C8MD00319J
- Veale CGL, Laming D, Swart T, et al. Exploring the Antiplasmodial 2-Aminopyridines as Potential Antitrypanosomal Agents. ChemMedChem. 2019;14(24):2034–2041. doi:10.1002/cmdc.201900492
- Tear WF, Bag S, Diaz-Gonzalez R, et al. Selectivity and physicochemical optimization of repurposed pyrazolo[1,5- b ]pyridazines for the treatment of human African trypanosomiasis. J Med Chem. 2020;63(2):756–783. doi:10.1021/acs.jmedchem.9b01741
- Diaz R, Luengo-Arratta SA, Seixas JD, et al. Identification and characterization of hundreds of potent and selective inhibitors of Trypanosoma brucei growth from a kinase-targeted library screening campaign. PLOS Negl Trop Dis. 2014;8(10):e3253. doi:10.1021/acs.jmedchem.9b01741
- Singh B, Diaz-Gonzalez R, Ceballos-Perez G, et al. Medicinal chemistry optimization of a diaminopurine chemotype: toward a lead for Trypanosoma brucei inhibitors. J Med Chem. 2020;63(17):9912–9927. doi:10.1021/acs.jmedchem.0c01017
- Bowyer PW, Tate EW, Leatherbarrow RJ, et al. N -Myristoyltransferase: a prospective drug target for protozoan parasites. ChemMedChem. 2008;3(3):402–408. doi:10.1002/cmdc.200700301
- Brand S, Cleghorn LAT, McElroy SP, et al. Discovery of a novel class of orally active trypanocidal n -myristoyltransferase inhibitors. J Med Chem. 2012;55(1):140–152. doi:10.1021/jm201091t
- Brand S, Norcross NR, Thompson S, et al. Lead optimization of a pyrazole sulfonamide series of trypanosoma brucei n -myristoyltransferase inhibitors: identification and evaluation of CNS penetrant compounds as potential treatments for stage 2 human African trypanosomiasis. J Med Chem. 2014;57(23):9855–9869. doi:10.1021/jm500809c
- Bayliss T, Robinson DA, Smith VC, et al. Design and synthesis of brain penetrant trypanocidal n -myristoyltransferase inhibitors. J Med Chem. 2017;60(23):9790–9806. doi:10.1021/acs.jmedchem.7b01255
- Ferrins L, Gazdik M, Rahmani R, et al. Pyridyl benzamides as a novel class of potent inhibitors for the kinetoplastid trypanosoma brucei. J Med Chem. 2014;57(15):6393–6402. doi:10.1021/jm500191u
- Burza S, Croft SL, Boelaert M. Leishmaniasis. The Lancet. 2018;392(10151):951–970. doi:10.1016/S0140-6736(18)31204-2
- Visceral leishmaniasis facts [Internet]. Geneva: Drugs for Neglected Diseases initiative; [ cited 2023 Aug 24]. Available from: https://dndi.org/diseases/visceral-leishmaniasis/facts/
- Leishmaniasis [Internet]. Geneva: World Health Organization; [ cited 2023 Aug 24]. Available from: www.who.int/news-room/fact-sheets/detail/leishmaniasis
- Moore E, Lockwood D. Treatment of visceral leishmaniasis. J Global Infect Dis. 2010;2(2):151. doi:10.4103/0974-777X.62883
- Nagle AS, Khare S, Kumar AB, et al. Recent developments in drug discovery for leishmaniasis and human African trypanosomiasis. Chem Rev. 2014;114(22):11305–11347. doi:10.1021/cr500365f
- Bhuniya D, Mukkavilli R, Shivahare R, et al. Aminothiazoles: hit to lead development to identify antileishmanial agents. Eur J Med Chem. 2015;102:582–593. doi:10.1016/j.ejmech.2015.08.013
- Coimbra ES, Antinarelli LMR, de A. Crispi M, et al. Synthesis, Biological Activity, and Mechanism of Action of 2-Pyrazyl and Pyridylhydrazone Derivatives, New Classes of Antileishmanial Agents. ChemMedChem. 2018;13(14):1387–1394. doi:10.1002/cmdc.201800328
- Evans AT, Croft SL, Peters W, et al. Antileishmanial effects of clofazimine and other antimycobacterial agents. Annals of Tropical Medicine & Parasitology. 1989;83(5):447–454. doi:10.1080/00034983.1989.11812371
- Namazi MR, Dastgheib L, Mazandarani J, et al. Clofazimine, an antimycobacterial with potent in vitro and in vivo leishmanicidal activity, is ineffective against cutaneous Leishmania major infection in humans. J Am Acad Dermatol. 2010;62(5):890–892. doi:10.1016/j.jaad.2009.07.011
- Barteselli A, Casagrande M, Basilico N, et al. Clofazimine analogs with antileishmanial and antiplasmodial activity. Bioorganic & Medicinal Chemistry. 2015;23(1):55–65. doi:10.1016/j.bmc.2014.11.028
- Bassanini I, Parapini S, Basilico N, et al. Novel hydrophilic riminophenazines as potent antiprotozoal agents. ChemMedChem. 2019;14(22):1940–1949. doi:10.1002/cmdc.201900522
- Paape D, Bell AS, Heal WP, et al. Using a non-image-based medium-throughput assay for screening compounds targeting n-myristoylation in intracellular leishmania amastigotes. PLOS Negl Trop Dis. 2014;8(12):e3363. doi:10.1371/journal.pntd.0003363
- Bell AS, Mills JE, Williams GP, et al. Selective inhibitors of protozoan protein N-myristoyltransferases as starting points for tropical disease medicinal chemistry programs. PLOS Negl Trop Dis. 2012;6(4):e1625. doi:10.1371/journal.pntd.0001625