RESUMEN
Quinolin-2-one represents an important and valuable chemical motif that possesses a wide variety of biological activities; however, the anti-influenza activities of quinolin-2-one-containing compounds were rarely reported. Herein, we describe the screening and identification of 3-aryl-quinolin-2-one derivatives as a novel class of antiviral agents. The 3-aryl-quinolinone derivatives were synthesized via an efficient copper-catalyzed reaction cascade that we previously developed. Using this synthetic method, preliminary structure-activity relationships of this scaffold against the influenza A virus infection were systematically explored. The most potent compound 34 displayed IC50 values of 2.14 and 4.88 µM against the replication of H3N2 (A/HK/8/68) and H1N1 (A/WSN/33) strains, respectively, without apparent cytotoxicity on MDCK cells. We further demonstrated that 27 and 34 potently inhibited the plaque formation of the IAV, rendering this scaffold attractive for pursuing novel anti-influenza agents.
Asunto(s)
Subtipo H1N1 del Virus de la Influenza A , Virus de la Influenza A , Gripe Humana , Animales , Perros , Humanos , Antivirales/uso terapéutico , Subtipo H3N2 del Virus de la Influenza A , Gripe Humana/tratamiento farmacológico , Células de Riñón Canino Madin DarbyRESUMEN
A series of 2-(tetrazol-5-yl)sulfonylacetamide derivatives were synthesized and evaluated for their in vitro inhibitory activity against Mycobacterium tuberculosis (Mtb) and Mycobacterium marinum (Mm). The most active compounds exhibited in vitro MIC90 values of 1.25 µg/mL against Mtb, but they were less effective against Mm (MIC90 ≥ 10 µg/mL). Despite the most active compounds having favourable physicochemical properties and one of them having a half-life of â¼3 h when incubated with mouse liver microsomes, two representative highly active compounds showed strong chemical reactivity to cysteine derivatives, as surrogate in vivo sulfur-centred nucleophiles, indicating excessive electrophilicity, and therefore, likely indiscriminate chemical reactivity in vivo, representing an unacceptably high risk of general toxicity, and low likelihood of being therapeutically effective.
Asunto(s)
Mycobacterium marinum , Mycobacterium tuberculosis , Animales , Ratones , Antituberculosos , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
Blapspirooxindoles A-C (1-3), three novel spirooxindole alkaloids with a unique spiro[chromane-4,3'-indoline]-2,2'-dione motif, blapcumaranons A and B (4 and 5), two new 2-cumaranon derivatives, blapoxindoles A-J (6-15), ten new oxindole alkaloid derivatives, along with one known compound (16), were isolated from the whole bodies of Blaps japanensis. Their structures including absolute configurations were determined by using spectroscopic, X-ray crystallographic, and computational methods. Compounds 1-11 and 13 exist as racemic mixtures in nature, and their (-)- and (+)-antipodes were separated by chiral HPLC. Biological evaluations of these compounds were determined with multiple assays including anti-tumor, anti-inflammatory, and renal protection activities in vitro. Several compounds displayed effective activity in one or more assays.
Asunto(s)
Alcaloides , Antineoplásicos , Escarabajos , Neoplasias , Animales , Escarabajos/química , Antineoplásicos/farmacología , Antineoplásicos/química , Alcaloides/farmacología , Oxindoles/farmacología , Estructura MolecularRESUMEN
Aberrantly activated Janus kinase 3 (JAK3) has been constantly detected in various immune disorders and hematopoietic cancers, suggesting its potential of being an attractive therapeutic target for these indications. Clinical benefits of drugs selectively targeting JAK3 versus pan-JAK inhibitors remain unclear. In this study, we report the design and synthesis of a new series of JAK3 covalent inhibitors with a pyrido[2,3-d]pyrimidin-7-one scaffold. After the extensive SAR study, compound 10f emerged to be the most potent JAK3 inhibitor with an IC50 value of 2.0 nM. It showed excellent selectively proliferation inhibitory activity against U937 cells harboring JAK3 M511I mutation, while remained weakly active to the other tested cancer cells. Compound 10f also dose-dependently inhibited the phosphorylation of JAK3 and its downstream signal STAT5 in U937 cells. Taken together, 10f may serve as a promising tool molecule for treating cancers with aberrantly activated JAK3.
Asunto(s)
Janus Quinasa 3 , Inhibidores de Proteínas Quinasas , Janus Quinasa 1 , Janus Quinasa 2 , Janus Quinasa 3/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-ActividadRESUMEN
The tropomyosin receptor kinases (TRKs) have been validated as effective targets in anticancer drug discovery. Two first-generation TRK inhibitors have been approved into market and displayed an encouraging therapeutic response in cancer patients harboring TRK fusion proteins. However, acquired resistance mediated by secondary TRK mutations especially in the xDFG motif remains an unsolved challenge in the clinic. Herein, we report the preclinical pharmacological results of JND4135, a new type II pan-TRK inhibitor, in overcoming TRK mutant resistance, including the xDFG mutations in vitro and in vivo. At a low nanomolar level, JND4135 displays a strong activity against wild-type TRKA/B/C and secondary mutations involving xDFG motif substitutions in kinase assays and cellular models; occupies the TRK proteins for an extended time; and has a slower dissociation rate than other TRK inhibitors. Moreover, by intraperitoneal injection, JND4135 exhibits tumor growth inhibition (TGI) of 81.0% at a dose of 40 mg/kg in BaF3-CD74-TRKA-G667C mice xenograft model. Therefore, JND4135 can be considered as a lead compound for drug discovery overcoming the resistance of TRK inhibitor drugs mediated by xDFG mutations.
Asunto(s)
Antineoplásicos , Neoplasias , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Humanos , Ratones , Mutación , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor trkA/genética , Receptor trkA/metabolismo , TropomiosinaRESUMEN
An aromatic trifluoromethyl ketone moiety was characterized as a new warhead for covalently reversible kinase inhibitor design to target the non-catalytic cysteine residue. Potent and selective covalently reversible inhibitors of FGFR4 kinase were successfully designed and synthesized by utilizing this new warhead. The binding mode of a representative inhibitor was fully characterized by using multiple technologies including MALDI-TOF mass spectrometry, dialysis assay and X-ray crystallographic studies etc. This functional group was also successfully applied to discovery of a new JAK3 inhibitor, suggesting its potential application in designing other kinase inhibitors.
Asunto(s)
Hidrocarburos Fluorados/farmacología , Janus Quinasa 3/antagonistas & inhibidores , Cetonas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Hidrocarburos Fluorados/síntesis química , Hidrocarburos Fluorados/química , Janus Quinasa 3/metabolismo , Cetonas/síntesis química , Cetonas/química , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-ActividadRESUMEN
With the emergence of multidrug-resistant strains of Mycobacterium tuberculosis (MDR-TB) and extensive drug-resistant strains (XDR-TB), there is an urgent need to develop novel drugs for the treatment of tuberculosis. Here, we designed and synthesized a series of 5-methylpyrimidopyridone analogues as potential antitubercular agents. The most potent compound 6q exhibited a MIC value of 4 µM in vitro against Mycobacterium tuberculosis. The antitubercular activities of the synthesized compounds were impacted by the amantadine and 2-chlorophenyl groups, and were enhanced by the presence of 3-methyl(4-dimethylamino)piperidinylphenyl. Molecular modeling and binding studies suggest that PknB is the potential molecular target of 5-methylpyrimidopyridone compounds. This study provides insights for the future development of new antimycobacterial agents with novel mechanisms of action.
Asunto(s)
Antituberculosos/farmacología , Descubrimiento de Drogas , Mycobacterium tuberculosis/efectos de los fármacos , Piridonas/farmacología , Animales , Antituberculosos/síntesis química , Antituberculosos/química , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Piridonas/síntesis química , Piridonas/química , Relación Estructura-Actividad , Células VeroRESUMEN
Fourteen ansamycin derivatives including seven new herbimycins G-L (1-6) and divergolide O (7), and seven known analogues were isolated from a culture broth of the marine-derived Streptomyces sp. SCSGAA 0027. Their complete structures were determined by detailed analysis of spectroscopic data and quantum chemical calculations. Compounds 1-5 and 7 featured an additional eight-membered O-heterocycle that has rarely been reported for ansamycins, and the Z,Z- and E,E-configurations for Δ2,Δ4 were reported for the first time in geldanamycin analogues. Compound 1 exhibited weak inhibition activity towards Hsp90α with an IC50 value of 96 µM, 2-5 showed mild cytotoxicity against four human cancer cell lines with IC50 values ranging from 13 µM to 86 µM, and 7 had moderate anti-HSV-1 activity with an IC50 value of 19 µM and very weak cytotoxicity towards Vero cell. The possible biosynthetic pathways for 1-5 were proposed. And their structure-bioactivity relationship was also discussed.
Asunto(s)
Antivirales/química , Rifabutina/análogos & derivados , Streptomyces/química , Antivirales/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/metabolismo , Herpesvirus Humano 1/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Conformación Molecular , Rifabutina/farmacología , Staphylococcus aureus/efectos de los fármacos , Estereoisomerismo , Streptomyces/metabolismo , Relación Estructura-ActividadRESUMEN
Pipajiains H-J (1-3), three new phenolic derivatives with an unusual sulfone group, pipajiamides A-C (4-6), three new amide derivatives, pipajiaine A (7), one new imidazole analogue, and pipajiaine B (8), a pair of new pyrrolidine derivatives, along with three known compounds were isolated from the insect Blaps japanensis. Their structures were identified by spectroscopic and computational methods. Chiral HPLC was used to separate the (-)- and (+)-antipodes of 4 and 8. Biological activities of all the new compounds against extracellular matrix in rat renal proximal tubular cells, human cancer cells (A549, Huh-7, and K562), COX-2, ROCK1, and JAK3 were evaluated. The results show that compounds 2, (+)-4, and (-)-4 are active against kidney fibrosis, whereas, compound 9 is active toward human cancer cells, inflammation, and JAK3 kinase.
Asunto(s)
Escarabajos/química , Compuestos de Nitrógeno/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Azufre/farmacología , Animales , Células Cultivadas , Teoría Funcional de la Densidad , Relación Dosis-Respuesta a Droga , Fibrosis/tratamiento farmacológico , Humanos , Janus Quinasa 3/antagonistas & inhibidores , Janus Quinasa 3/metabolismo , Estructura Molecular , Compuestos de Nitrógeno/química , Compuestos de Nitrógeno/aislamiento & purificación , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/aislamiento & purificación , Ratas , Relación Estructura-Actividad , Azufre/química , Azufre/aislamiento & purificación , Quinasas Asociadas a rho/antagonistas & inhibidores , Quinasas Asociadas a rho/metabolismoRESUMEN
Nicotinamide phosphoribosyltransferase (NAMPT) has emerged as a promising target for the discovery of anticancer drugs. Based on NAMPT inhibitor FK866 that has been advanced into phase II trial, we identified a trans-3-(pyridin-3-yl)acrylamide compound 13 incorporating with a biarylsulfanilamide moiety as a new NAMPT inhibitor. Further structure-activity relationship (SAR) exploration led to additional biarylsulfanilamide-derived compounds with high in vitro NAMPT inhibitory potency and antiproliferative activity. In particular, compound 23, the most potent NAMPT inhibitor (IC50â¯=â¯5.08â¯nM), showed single-digit nanomolar antiproliferative activity against DU145, Hela, and H1975 cells with IC50 values of 2.90â¯nM, 2.34â¯nM, and 2.24â¯nM, respectively, and even subnanomolar level against K562, MCF-7, and HUH7 cells with IC50 values of 0.46â¯nM, 0.23â¯nM and 0.53â¯nM, respectively. Our findings provided promising lead compounds for the discovery of more potent NAMPT inhibitors as anticancer drugs.
Asunto(s)
Neoplasias/tratamiento farmacológico , Nicotinamida Fosforribosiltransferasa/antagonistas & inhibidores , Línea Celular Tumoral , Humanos , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
Indoleamine 2,3-dioxygenase 1 (IDO1) is an attractive therapeutic target for the treatment of cancer, chronic viral infections and neurological disorders characterized by pathological immune stimulation. Herein, a series of known metal-chelating ubiquinone derivatives were designed, synthesized and evaluated for the IDO1 inhibiting activities. The docking studies showed that the compounds 11, 16, 18 and coenzyme-Q1 exhibited different binding modes to IDO1 protein. Among these compounds, the most active compound is 16d with an IC50 of 0.13⯵M in enzymatic assay. The results reveal that a possible halogen bonding interaction between the bromine atom (3-Br) and Cys129 significantly enhances the inhibition activity against IDO1. This study provides structural insights of the interactions between ubiquinone analogues and IDO1 protein for the further modification and optimization.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Ubiquinona/análogos & derivados , Sitios de Unión , Dominio Catalítico , Supervivencia Celular/efectos de los fármacos , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Células HEK293 , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Ubiquinona/metabolismo , Ubiquinona/farmacologíaRESUMEN
Three pairs of meroterpenoids (±) cochlearoids N-P (1-3) were isolated from the fruiting bodies of Ganoderma cochlear. Their structures including absolute configurations were assigned by spectroscopic techniques. All the isolated compounds were tested for their inhibitory activities toward BRD4, human cancer cells, and micro-organisms. The results show that the enantiomers of (±)-1 are BRD4 inhibitors, (-)-1 and (+)-3 are cytotoxic against human cancer cells (K562) with IC50 values of 7.68 and 6.68 µM, respectively. Besides compounds (±)-2 and (±)-3 exhibit potent inhibitory activity against Staphylococcus aureus with IC50 values in the range of 5.43-17.99 µM.
Asunto(s)
Ganoderma/química , Fenoles/química , Terpenos/química , Antibacterianos/química , Antibacterianos/farmacología , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacología , Línea Celular Tumoral , Cuerpos Fructíferos de los Hongos/química , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Proteínas Nucleares/antagonistas & inhibidores , Fenoles/farmacología , Terpenos/farmacología , Factores de Transcripción/antagonistas & inhibidoresRESUMEN
In the present study, endoperoxide and 4-anilinoqnazoline were conjugated to obtain a series of compounds. These conjugates exhibited high antiproliferative potency against a number of cancer cell lines, including the epidermal growth factor receptor (EGFR) L858R/T790M mutant cell. Compound 5 was selected as a representative for mechanistic study. Further experiments revealed the conjugate's reactive oxygen species (ROS) generating ability, apoptosis inducing activity and involvement in EGFR downstream signaling pathways.
Asunto(s)
Antineoplásicos/farmacología , Peróxidos/química , Quinazolinas/química , Antineoplásicos/química , Línea Celular Tumoral , Receptores ErbB/antagonistas & inhibidores , Humanos , Concentración 50 InhibidoraRESUMEN
Spiroapplanatumines A-Q (1-12, 14-16, 18, and 20), new spiro meroterpenoids respectively bearing a 6/5/7 or 6/5/5 ring system, along with three known compounds, spirolingzhines A, B, and D, were isolated from the fruiting bodies of the fungus Ganoderma applanatum. Their structures including absolute configurations were assigned by using spectroscopic methods, ECD and 13C NMR calculations, and single-crystal X-ray diffraction analysis. Biological evaluation of all the compounds disclosed that compounds 7 and 8 inhibited JAK3 kinase with IC50 values of 7.0 ± 3.2 and 34.8 ± 21.1 µM, respectively.
Asunto(s)
Agaricales/química , Cuerpos Fructíferos de los Hongos/química , Ganoderma/química , Janus Quinasa 3/antagonistas & inhibidores , Terpenos/aislamiento & purificación , Terpenos/farmacología , Triterpenos/aislamiento & purificación , Triterpenos/farmacología , Concentración 50 Inhibidora , Janus Quinasa 3/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Terpenos/química , Triterpenos/química , Difracción de Rayos XRESUMEN
Three new polyketides, chaetochromones A - C (1 - 3), together with a chromone (4), were isolated from the ethyl acetate extract of mangrove-derived fungus Phomopsis sp. SCSIO 41006. Their structures were elucidated by means of spectroscopic techniques (UV, IR, MS, 1D- and 2D-NMR). The absolute configurations of the new compounds were established by CD data.
Asunto(s)
Hongos/metabolismo , Policétidos/química , Rhizophoraceae/microbiología , Células A549 , Antiinfecciosos/química , Antiinfecciosos/aislamiento & purificación , Antiinfecciosos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cromonas/química , Cromonas/aislamiento & purificación , Cromonas/farmacología , Dicroismo Circular , Hongos/clasificación , Hongos/aislamiento & purificación , Humanos , Células K562 , Espectroscopía de Resonancia Magnética , Conformación Molecular , Filogenia , Policétidos/aislamiento & purificación , Policétidos/farmacología , Policétidos/toxicidad , Salmonella typhi/efectos de los fármacos , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría Ultravioleta , Staphylococcus aureus/efectos de los fármacosRESUMEN
A series of novel 4,5,6-trisubstituted pyrimidines were designed as potent covalent Bruton's tyrosine kinase (BTK) inhibitors based on the structure of ibrutinib by using a ring-opening strategy. Among these derivatives, compound I1 exhibited the most potent inhibitory activity with an IC50 value of 0.07µM. The preliminary structure-activity relationship was discussed and the primary amino group at the C-4 position of pyrimidine was crucial for maintaining BTK activity. Furthermore, molecular dynamics simulations and binding free energy calculations were performed for three inhibitor-BTK complexes to determine the probable binding model, which provided a comprehensive guide for further structural modification and optimization.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/química , Adenina/análogos & derivados , Agammaglobulinemia Tirosina Quinasa , Dominio Catalítico , Enlace de Hidrógeno , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Piperidinas , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Tirosina Quinasas/química , Pirazoles/química , Pirimidinas/síntesis química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Five new highly oxygenated α-pyrone merosesquiterpenoids, ochraceopones A-E (1-5), together with one new double bond isomer of asteltoxin, isoasteltoxin (6), and two known asteltoxin derivatives, asteltoxin (7) and asteltoxin B (8), were isolated from an Antarctic soil-derived fungus, Aspergillus ochraceopetaliformis SCSIO 05702. Their structures were determined through extensive spectroscopic analysis, CD spectra, quantum mechanical calculations, and X-ray single-crystal diffraction. Ochraceopones A-D (1-4) are the first examples of α-pyrone merosesquiterpenoids possessing a linear tetracyclic carbon skeleton, which has not been previously described. All the isolated compounds were tested for their antiviral, cytotoxic, antibacterial, and antitubercular activities. Among these compounds, ochraceopone A (1), isoasteltoxin (6), and asteltoxin (7) exhibited antiviral activities against the H1N1 and H3N2 influenza viruses with IC50 values of >20.0/12.2 ± 4.10, 0.23 ± 0.05/0.66 ± 0.09, and 0.54 ± 0.06/0.84 ± 0.02 µM, respectively. A possible biosynthetic pathway for ochraceopones A-E (1-5) was proposed.
Asunto(s)
Antivirales/aislamiento & purificación , Antivirales/farmacología , Pironas/aislamiento & purificación , Pironas/farmacología , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/farmacología , Regiones Antárticas , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Antibacterianos/farmacología , Antivirales/química , Cristalografía por Rayos X , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H3N2 del Virus de la Influenza A/efectos de los fármacos , Concentración 50 Inhibidora , Biología Marina , Conformación Molecular , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Pironas/química , Sesquiterpenos/química , Microbiología del SueloRESUMEN
Blapsols A-D (1-4), four new compounds possessing a 2,3-dihydrobenzo[b][1,4]dioxin group, together with five known N-acetyldopamine dimers (5-9), were isolated from Blaps japanensis. Their structures including the absolute configuration of (+)-1 were determined by means of spectroscopic and X-ray crystallographic methods. Chiral HPLC was used to separate (-)- and (+)-enantiomers of compounds 1-4, which were isolated from this insect as racemic mixtures. All the compounds were found to have inhibitory effects towards COX-2 with IC50 values in the range of 1.3-17.8µM.
Asunto(s)
Escarabajos/química , Ciclooxigenasa 1/química , Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa/química , Animales , Escarabajos/metabolismo , Cristalografía por Rayos X , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Dioxinas/química , Espectroscopía de Resonancia Magnética , Conformación Molecular , EstereoisomerismoRESUMEN
A series of 3,5-disubstitute-4-alkynylisoxazole derivatives were designed and synthesized through palladium(II)-copper(I) catalyzed Sonogashira cross-coupling reaction of an alkynyl moiety and an isoxazole scaffold as novel HSP90 inhibitors. The resultant compounds displayed moderate to potent binding affinity to HSP90 proteins, and also demonstrated good cell growth inhibitory activity against various cancer cell lines (A549, K562, MCF-7, DU145 and Hela). Some compounds (18d, 18e, 19a, 19d, 20c and 20q) show similar or better binding affinity towards HSP90α and HSP90ß comparing to NVP-AUY922. In addition, compounds 18e, 19a and 20q exhibited potent inhibitory activity against various human cancer cell lines.
Asunto(s)
Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Isoxazoles/química , Apoptosis/efectos de los fármacos , Sitios de Unión , Catálisis , Dominio Catalítico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cobre/química , Ensayos de Selección de Medicamentos Antitumorales , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Isoxazoles/síntesis química , Isoxazoles/farmacología , Isoxazoles/toxicidad , Simulación del Acoplamiento Molecular , Paladio/química , Resorcinoles/toxicidad , Relación Estructura-ActividadRESUMEN
Given the rise of parasite resistance to all currently used antimalarial drugs, the identification of novel chemotypes with unique mechanisms of action is of paramount importance. Since Plasmodium expresses a number of aspartic proteases necessary for its survival, we have mined antimalarial datasets for drug-like aspartic protease inhibitors. This effort led to the identification of spiropiperidine hydantoins, bearing similarity to known inhibitors of the human aspartic protease ß-secretase (BACE), as new leads for antimalarial drug discovery. Spiropiperidine hydantoins have a dynamic structure-activity relationship profile with positions identified as being tolerant of a variety of substitution patterns as well as a key piperidine N-benzyl phenol pharmacophore. Lead compounds 4e (CWHM-123) and 12k (CWHM-505) are potent antimalarials with IC50 values against Plasmodium falciparum 3D7 of 0.310 µM and 0.099 µM, respectively, and the former features equivalent potency on the chloroquine-resistant Dd2 strain. Remarkably, these compounds do not inhibit human aspartic proteases BACE, cathepsins D and E, or Plasmodium plasmepsins II and IV despite their similarity to known BACE inhibitors. Although the current leads suffer from poor metabolic stability, they do fit into a drug-like chemical property space and provide a new class of potent antimalarial agents for further study.