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1.
J Nat Prod ; 86(10): 2368-2378, 2023 10 27.
Article in English | MEDLINE | ID: mdl-37779357

ABSTRACT

The first semisynthetic routes toward terrestrial anti-inflammatory natural products linariophyllene A-C and the refined route toward marine natural product rumphellolide H are presented. Among the synthesized target compounds, the correct structure of linariophyllene A was determined to be the diastereomer of the originally proposed structure with an inverted stereocenter at the secondary alcohol. The proposed structures of linariophyllene B and rumphellolide H were confirmed. However, the correct structure of linariophyllene C was found to be the diastereomer of the originally proposed structure with an inverted stereocenter at the tertiary carbon of the epoxide moiety. The structures of linariophyllenes A-C and rumphellolide H were unequivocally confirmed by single-crystal X-ray diffractometry. The obtained results enabled the proposal of the biosynthetic origins of the aforementioned natural products and bolstered the diversity of available sesquiterpenoids. Linariophyllenes A-C and rumphellolide H were obtained in sufficient amounts to further expand their bioactivity profile and utility as reference standards in future studies of chemical constituents of terrestrial and marine organisms.


Subject(s)
Aquatic Organisms , Biological Products , Aquatic Organisms/chemistry , Biological Products/chemistry , Biosynthetic Pathways , Molecular Structure
2.
J Med Chem ; 66(15): 10658-10680, 2023 08 10.
Article in English | MEDLINE | ID: mdl-37505188

ABSTRACT

The Plasmodium falciparum aspartic protease plasmepsin X (PMX) is essential for the egress of invasive merozoite forms of the parasite. PMX has therefore emerged as a new potential antimalarial target. Building on peptidic amino alcohols originating from a phenotypic screening hit, we have here developed a series of macrocyclic analogues as PMX inhibitors. Incorporation of an extended linker between the S1 phenyl group and S3 amide led to a lead compound that displayed a 10-fold improved PMX inhibitory potency and a 3-fold improved half-life in microsomal stability assays compared to the acyclic analogue. The lead compound was also the most potent of the new macrocyclic compounds in in vitro parasite growth inhibition. Inhibitor 7k cleared blood-stage P. falciparum in a dose-dependent manner when administered orally to infected humanized mice. Consequently, lead compound 7k represents a promising orally bioavailable molecule for further development as a PMX-targeting antimalarial drug.


Subject(s)
Antimalarials , Peptidomimetics , Mice , Animals , Antimalarials/pharmacology , Antimalarials/metabolism , Peptidomimetics/pharmacology , Peptidomimetics/metabolism , Protease Inhibitors/pharmacology , Protease Inhibitors/metabolism , Aspartic Acid Endopeptidases , Plasmodium falciparum/metabolism , Protozoan Proteins
3.
J Chem Inf Model ; 62(13): 3263-3273, 2022 07 11.
Article in English | MEDLINE | ID: mdl-35712895

ABSTRACT

Selectivity is a major issue in the development of drugs targeting pathogen aspartic proteases. Here, we explore the selectivity-determining factors by studying specifically designed malaria aspartic protease (plasmepsin) open-flap inhibitors. Metadynamics simulations are used to uncover the complex binding/unbinding pathways of these inhibitors and describe the critical transition states in atomistic resolution. The simulation results are compared with experimentally determined enzymatic activities. Our findings demonstrate that plasmepsin inhibitor selectivity can be achieved by targeting the flap loop with hydrophobic substituents that enable ligand binding under the flap loop, as such a behavior is not observed for several other aspartic proteases. The ability to estimate the selectivity of compounds before they are synthesized is of considerable importance in drug design; therefore, we expect that our approach will be useful in selective inhibitor designs against not only aspartic proteases but also other enzyme classes.


Subject(s)
Antimalarials , Aspartic Acid Endopeptidases , Plasmodium falciparum , Protease Inhibitors , Antimalarials/chemistry , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid Endopeptidases/chemistry , Computer Simulation , Drug Design , Malaria/drug therapy , Plasmodium falciparum/drug effects , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Protozoan Proteins/chemistry
4.
Org Biomol Chem ; 20(12): 2455-2461, 2022 03 23.
Article in English | MEDLINE | ID: mdl-35254363

ABSTRACT

The convergent biomimetic gram-scale synthesis of disesquiterpenoid ester rumphellolide J is described. 4ß,8ß-Epoxycaryophyllan-5-ol was prepared in 67% yield (1.4 g) from naturally ambudant (-)-ß-caryophyllene. (+)-Rumphellaoic acid A was obtained in 46% yield (2.2 g) from (-)-caryophyllene oxide. The synthesised (+)-rumphellaoic acid had an opposite specific rotation compared to that of (-)-rumphellaoic acid A isolated from nature, indicating possible occurrence of (+)-ß-caryophyllene in Rumphella antipathies and Psidium guajava. Esterification of (+)-rumphellaoic acid A via acyl fluoride and alkoxide of 4ß,8ß-epoxycaryophyllan-5-ol gave rumphellolide J in 70% yield (1.65 g). The same structure for the synthesized product and natural isolate was proven despite the opposite specific rotation value of the intermediate acid. The short access to the terpenoids provides a material for further investigations of biological activities and valuable reference standards for the analysis of the chemical composition of various natural sources.


Subject(s)
Anthozoa , Psidium , Animals , Biomimetics , Psidium/chemistry , Terpenes
5.
J Nat Prod ; 83(6): 2004-2009, 2020 06 26.
Article in English | MEDLINE | ID: mdl-32538090

ABSTRACT

The first semisynthetic route toward rumphellaones B (2) and C (3) and their C-8 epimers as well as the shortest synthesis of rumphellaone A (1) and its C-8 epimer from the most accessible sesquiterpene, ß-caryophyllene (4), is presented. Synthetic routes involved caryophyllonic acid as a key intermediate, which was converted to rumphellaone A (and epimer) via acid-catalyzed lactonization and rumphellaone C (and epimer) using one-pot epoxidation-lactonization. Rumphellaone B (2) and its epimer were obtained from rumphellaone A (1) and its epimer, respectively, using Saegusa-Ito oxidation. The absolute configuration at C-8 was confirmed by single-crystal X-ray analysis of rumphellaone B (2) and an acylated derivative of rumphellaone C.


Subject(s)
Polycyclic Sesquiterpenes/chemistry , Sesquiterpenes/chemical synthesis , Sesquiterpenes/pharmacology , Sesterterpenes/chemical synthesis , Sesterterpenes/pharmacology , Animals , Anthozoa/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Isomerism , Lactones/chemical synthesis , Molecular Structure , Sesquiterpenes/chemistry , X-Ray Diffraction
6.
SLAS Discov ; 24(3): 398-413, 2019 03.
Article in English | MEDLINE | ID: mdl-30616481

ABSTRACT

Compound screening in biological assays and subsequent optimization of hits is indispensable for the development of new molecular research tools and drug candidates. To facilitate such discoveries, the European Research Infrastructure EU-OPENSCREEN was founded recently with the support of its member countries and the European Commission. Its distributed character harnesses complementary knowledge, expertise, and instrumentation in the discipline of chemical biology from 20 European partners, and its open working model ensures that academia and industry can readily access EU-OPENSCREEN's compound collection, equipment, and generated data. To demonstrate the power of this collaborative approach, this perspective article highlights recent projects from EU-OPENSCREEN partner institutions. These studies yielded (1) 2-aminoquinazolin-4(3 H)-ones as potential lead structures for new antimalarial drugs, (2) a novel lipodepsipeptide specifically inducing apoptosis in cells deficient for the pVHL tumor suppressor, (3) small-molecule-based ROCK inhibitors that induce definitive endoderm formation and can potentially be used for regenerative medicine, (4) potential pharmacological chaperones for inborn errors of metabolism and a familiar form of acute myeloid leukemia (AML), and (5) novel tankyrase inhibitors that entered a lead-to-candidate program. Collectively, these findings highlight the benefits of small-molecule screening, the plethora of assay designs, and the close connection between screening and medicinal chemistry within EU-OPENSCREEN.


Subject(s)
Cooperative Behavior , Drug Discovery/methods , Drug Evaluation, Preclinical , Europe , High-Throughput Screening Assays , Humans , Structure-Activity Relationship
7.
Bioorg Med Chem ; 26(9): 2488-2500, 2018 05 15.
Article in English | MEDLINE | ID: mdl-29636223

ABSTRACT

2-Aminoquinazolin-4(3H)-ones were previously discovered as perspective leads for antimalarial drug development targeting the plasmepsins. Here we report the lead optimization studies with the aim to reduce inhibitor lipophilicity and increase selectivity versus the human aspartic protease Cathepsin D. Exploiting the solvent exposed area of the enzyme provides an option to install polar groups (R1) the 5-position of 2-aminoquinazolin-4(3H)-one to inhibitors such as carboxylic acid without scarifying enzymatic potency. Moreover, introduction of R1 substituents increased selectivity factors of compounds in this series up to 100-fold for Plm II, IV vs CatD inhibition. The introduction of flap pocket substituent (R2) at 7-postion of 2-aminoquinazolin-4(3H)-one allows to remove Ph group from THF ring without notably impairing Plm inhibitory potency. Based on these findings, inhibitors were developed, which show Plm II and IV inhibitory potency in low nanomolar range and remarkable selectivity against Cathepsin D along with decreased lipophilicity and increased solubility.


Subject(s)
Aspartic Acid Endopeptidases/antagonists & inhibitors , Protease Inhibitors/chemistry , Protozoan Proteins/antagonists & inhibitors , Quinazolinones/chemistry , Aspartic Acid Endopeptidases/chemistry , Binding Sites , Cathepsin D/chemistry , Hydrophobic and Hydrophilic Interactions , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Plasmodium falciparum/enzymology , Protease Inhibitors/chemical synthesis , Protozoan Proteins/chemistry , Quinazolinones/chemical synthesis , Solubility , Structure-Activity Relationship
8.
Chem Commun (Camb) ; 52(63): 9777-80, 2016 Jul 28.
Article in English | MEDLINE | ID: mdl-27419251

ABSTRACT

C-H arylations were accomplished with a user-friendly heterogeneous palladium catalyst in the biomass-derived γ-valerolactone (GVL) as an environmentally-benign reaction medium. The user-friendly protocol was characterized by ample substrate scope and high functional group tolerance in the C-H arylation of 1,2,3-triazoles, and the palladium catalyst could be recycled and reused in the C-H activation process.


Subject(s)
Hydrocarbons, Aromatic/chemistry , Lactones/chemistry , Palladium/chemistry , Triazoles/chemistry , Biomass , Catalysis , Green Chemistry Technology
9.
Antimicrob Agents Chemother ; 60(10): 6359-61, 2016 10.
Article in English | MEDLINE | ID: mdl-27431224

ABSTRACT

Bacterial aminoacyl-tRNA synthetases (aaRSs) represent promising antibacterial drug targets. Unfortunately, the aaRS inhibitors that have to date reached clinical trials are subject to rapid resistance development through mutation, a phenomenon that limits their potential clinical utility. Here, we confirm the intuitively correct idea that simultaneous targeting of two different aaRS enzymes prevents the emergence of spontaneous bacterial resistance at high frequency, a finding that supports the development of multitargeted anti-aaRS therapies.


Subject(s)
Amino Acyl-tRNA Synthetases/antagonists & inhibitors , Anti-Bacterial Agents/pharmacology , Drug Resistance, Bacterial/drug effects , Enzyme Inhibitors/pharmacology , Staphylococcus aureus/drug effects , Boron Compounds/pharmacology , Diamines/pharmacology , Microbial Sensitivity Tests , Molecular Targeted Therapy , Mupirocin/pharmacology , Mutation Rate , Staphylococcus aureus/genetics , Thiophenes/pharmacology
10.
Antimicrob Agents Chemother ; 60(5): 3219-21, 2016 05.
Article in English | MEDLINE | ID: mdl-26976861

ABSTRACT

GSK2251052 is a broad-spectrum antibacterial inhibitor of leucyl tRNA-synthetase (LeuRS) that has been evaluated in phase II clinical trials. Here, we report the identification of a clinical isolate of Staphylococcus aureus that exhibits reduced susceptibility to GSK2251052 without prior exposure to the compound and demonstrate that this phenotype is attributable to a single amino acid polymorphism (P329) within the editing domain of LeuRS.


Subject(s)
Anti-Bacterial Agents/pharmacology , Boron Compounds/pharmacology , Polymorphism, Genetic/genetics , Staphylococcus aureus/drug effects , Bacterial Proteins/genetics , Leucine-tRNA Ligase/genetics , Leucine-tRNA Ligase/metabolism , Staphylococcus aureus/genetics , Staphylococcus aureus/metabolism
11.
J Med Chem ; 59(1): 374-87, 2016 Jan 14.
Article in English | MEDLINE | ID: mdl-26670264

ABSTRACT

2-Aminoquinazolin-4(3H)-ones were identified as a novel class of malaria digestive vacuole plasmepsin inhibitors by using NMR-based fragment screening against Plm II. Initial fragment hit optimization led to a submicromolar inhibitor, which was cocrystallized with Plm II to produce an X-ray structure of the complex. The structure showed that 2-aminoquinazolin-4(3H)-ones bind to the open flap conformation of the enzyme and provided clues to target the flap pocket. Further improvement in potency was achieved via introduction of hydrophobic substituents occupying the flap pocket. Most of the 2-aminoquinazolin-4(3H)-one based inhibitors show a similar activity against digestive Plms I, II, and IV and >10-fold selectivity versus CatD, although varying the flap pocket substituent led to one Plm IV selective inhibitor. In cell-based assays, the compounds show growth inhibition of Plasmodium falciparum 3D7 with IC50 ∼ 1 µM. Together, these results suggest 2-aminoquinazolin-4(3H)-ones as perspective leads for future development of an antimalarial agent.


Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Aspartic Acid Endopeptidases/antagonists & inhibitors , Quinazolines/chemical synthesis , Quinazolines/pharmacology , 3T3 Cells , Animals , Cell Survival/drug effects , Crystallography, X-Ray , Malaria/drug therapy , Malaria/parasitology , Mice , Models, Molecular , Plasmodium falciparum/drug effects , Structure-Activity Relationship
12.
J Org Chem ; 80(11): 5934-43, 2015 Jun 05.
Article in English | MEDLINE | ID: mdl-25941908

ABSTRACT

A diastereoselective synthesis of 4-vinyl oxazolines syn-2 was developed based on an acid-catalyzed cyclization of bistrichloroacetimidates (E)-1. The reaction likely involves an allyl carbenium ion intermediate in which the adjacent stereocenter directs the stereoselectivity for C-N bond formation. Oxazolines syn-2 were transformed to C-quaternary threoninol, threoninal, and threonine derivatives which can be further incorporated into complex natural compounds.


Subject(s)
Allyl Compounds/chemistry , Amino Alcohols/chemistry , Butylene Glycols/chemistry , Imidoesters/chemical synthesis , Oxazoles/chemical synthesis , Vinyl Compounds/chemistry , Cyclization , Imidoesters/chemistry , Molecular Structure , Oxazoles/chemistry , Stereoisomerism
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