ABSTRACT
Guided by structure-based design, we synthesized two novel series of potent inhibitors of BACE1 and generated extensive SAR around both the prime and non-prime side binding pockets. The key feature of both series is a cyclic amine motif specifically crafted to achieve interactions with both the flap and with the S2' pocket.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Drug Design , Imidazolidines/chemical synthesis , Imidazolidines/pharmacology , Piperazines/chemical synthesis , Piperazines/pharmacology , Animals , Crystallography, X-Ray , Disease Models, Animal , Humans , Imidazolidines/chemistry , Mice , Mice, Transgenic , Models, Molecular , Molecular Conformation , Molecular Structure , Piperazines/chemistry , Structure-Activity RelationshipABSTRACT
Based on lead compound 1 identified from the patent literature, we developed novel patentable BACE-1 inhibitors by introducing a cyclic amine scaffold. Extensive SAR studies on both pyrrolidines and piperidines ultimately led to inhibitor 2f, one of the most potent inhibitors synthesized to date.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Piperidines/chemistry , Piperidines/pharmacology , Protease Inhibitors/chemistry , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Amyloid Precursor Protein Secretases/chemistry , Amyloid Precursor Protein Secretases/metabolism , Aspartic Acid Endopeptidases/chemistry , Aspartic Acid Endopeptidases/metabolism , Cell Line , Crystallography, X-Ray , Humans , Hydrogen Bonding , Models, Molecular , Piperidines/chemical synthesis , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Pyrrolidines/chemical synthesis , Structure-Activity RelationshipABSTRACT
Over 20 new, cyclic, peroxy ketals have been prepared via a two-step protocol starting with readily available aryl methyl ketones. Structure-activity correlations using in vitro antimalarial data as a guide for optimization of potency have led to the design and synthesis of seven new peroxides that have IC50 values of 31-85 nM (artemisinin IC50 = 8.4 nM). Some SAR generalizations are discussed.
Subject(s)
Antimalarials , Artemisinins , Drug Design , Heterocyclic Compounds , Animals , Antimalarials/chemical synthesis , Antimalarials/chemistry , Antimalarials/pharmacology , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Plasmodium falciparum/drug effects , Sesquiterpenes/pharmacology , Structure-Activity RelationshipABSTRACT
On the basis of a mechanistic understanding of the mode of action of artemisinin-like antimalarials, a series of structurally simple 3-aryl-1,2,4-trioxanes 5 was designed and was prepared in three to five operations from commercial reactants. The 3-aryl group was attached in each case as a nucleophile. In an electronically complementary fashion, 3-(fluoroalkyl)-trioxanes 6 were prepared via attachment of electrophilic fluoroalkyl esters. Both in vitro and in vivo antimalarial evaluations of these new trioxanes showed 12 beta-methoxy-3-aryltrioxanes 5g, 5j, 5k, and 51 to be highly potent, with crystalline fluorobenzyl ether trioxane 5k especially potent even when administered to rodents orally. As shown by rearrangement of hexamethyl Dewar benzene into hexamethylbenzene, iron-induced degradation of some of these 3-aryltrioxanes 5 involves generation of high-valent iron oxo species that might kill malaria parasites.
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Administration, Oral , Animals , Antimalarials/administration & dosage , Antimalarials/chemistry , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Drug Evaluation, Preclinical , Mice , Plasmodium berghei , Plasmodium falciparum/drug effects , Structure-Activity RelationshipABSTRACT
Novel C4-(hydroxyalkyl)trioxanes 5d and 5e were designed and synthesized based on an understanding of the molecular mechanism of action of similar 1,2,4-trioxanes structurally related to the antimalarial natural product artemisinin (1). In vitro efficacies of these two new pairs of C4-diastereomers against chloroquine-sensitive Plasmodium falciparum support conclusions about the importance to antimalarial activity of formation of a C4 radical by a 1,5-hydrogen atom abstraction. Derivatives 6, 7, and 21 of C4 beta-substituted trioxane alcohols 4a, 5d, and 5e were prepared, each in a single-step, high-yielding transformation. Four of these new analogues, 6a-c and 7, are potent in vitro antimalarials, having 140 to 50% of the efficacy of the natural trioxane artemisinin (1).
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Artemisinins , Heterocyclic Compounds/chemical synthesis , Sesquiterpenes/pharmacology , Animals , Antimalarials/chemistry , Chloroquine/pharmacology , Drug Design , Drug Evaluation, Preclinical , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Plasmodium falciparum/drug effects , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Currently, the treatment of falciparum malaria is seriously compromised by spreading drug resistance. We studied the effects of camptothecin, a potent and specific topoisomerase I inhibitor, on erythrocytic malaria parasites in vitro. In Plasmodium falciparum, camptothecin trapped protein-DNA complexes, inhibited nucleic acid biosynthesis, and was cytotoxic. These results provide proof for the concept that topoisomerase I is a vulnerable target for new antimalarial drug development.
Subject(s)
Camptothecin/pharmacology , Enzyme Inhibitors/pharmacology , Plasmodium falciparum/drug effects , Topoisomerase I Inhibitors , Animals , Erythrocytes/parasitology , Plasmodium falciparum/enzymologyABSTRACT
A series of 4,8-dimethyl-4-phenylsulfonylmethyl-2,3-dioxabicyclo[3.3.1]+ ++nonanes, carrying a variety of substituents at position-8 (4) were prepared by a short and efficient method from R-(+)-limonene. Key reactions include thiol oxygen cooxidation, and alkylation and acylation of a sterically hindered tertiary alcohol compatible with the endoperoxy functionality. Some of compounds 4, which are structurally related to yingzhaosu A (2), were found to exhibit in vitro antimalarial activity comparable to that of artemisinin (1) and superior to that of arteflene (3).
Subject(s)
Antimalarials/chemical synthesis , Plasmodium falciparum/drug effects , Sulfones/chemical synthesis , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Chloroquine/pharmacology , Drugs, Chinese Herbal , Models, Molecular , Molecular Conformation , Molecular Structure , Peroxides , Sesquiterpenes/chemistry , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacologyABSTRACT
A series of tetracyclic and tricyclic trioxane dimers has been prepared with ether and ester tethers of varying length and flexibility. Several of these trioxane dimers have been found to have potent and potentially therapeutically valuable antimalarial, antiproliferative, and antitumor activities in vitro.
