ABSTRACT
Starting from cyclopentadiene, two racemic mixtures of 4-aminocyclopentane-1,3-diols were prepared in 8 steps and characterized. Structure determination proved the anticipated trans-orientation of the two oxygen atoms with respect to the plane of the ring. The fragment-like new compounds are small and hydrophilic, devoid of rotatable bonds, and offer stereochemically defined attachment points for substituents. Thus, these platforms for diversity are suitable starting points for the construction of combinatorial libraries of lead-like 4-amidocyclopentane-1,3-diols or natural product analogs. As a proof of concept, cyclopentanoid anandamide analogs were prepared using these molecular platforms and evaluated as tools for the investigation of unresolved issues in the molecular biology of anandamide.
Subject(s)
Amines/chemistry , Arachidonic Acids/chemical synthesis , Cyclopentanes/chemistry , Endocannabinoids/chemical synthesis , Polyunsaturated Alkamides/chemical synthesis , Arachidonic Acids/chemistry , Combinatorial Chemistry Techniques , Drug Design , Endocannabinoids/chemistry , Hydrophobic and Hydrophilic Interactions , Models, Molecular , Molecular Structure , Polyunsaturated Alkamides/chemistry , Small Molecule Libraries , StereoisomerismABSTRACT
A series of 30 adenosine derivatives with three different substituents at the N(6)-position were prepared in order to evaluate their potential to inhibit the pathogenic protozoa Plasmodium falciparum and Trypanosoma brucei in vitro. The rationale for synthesis of these structures was the high probability of interactions with multiple adenosine associated targets and the assumption that N(6)-substitutents should increase stability against adenosine deaminases and allow the molecules to diffuse across parasite membranes. Starting from inosine, the new compounds were prepared as single isomers using a polymer-assisted acylation protocol enabling the straightforward isolation of the target compounds in pure form. Three of the compounds displayed anti-plasmodial and one anti-trypanosomal activity in the single digit micromolar concentration range.
Subject(s)
Antimalarials/chemical synthesis , Deoxyadenosines/chemical synthesis , Plasmodium falciparum/drug effects , Trypanocidal Agents/chemical synthesis , Trypanosoma brucei brucei/drug effects , Acylation , Adenosine/metabolism , Antimalarials/chemistry , Antimalarials/pharmacology , Deoxyadenosines/chemistry , Deoxyadenosines/pharmacology , Inhibitory Concentration 50 , Models, Molecular , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacologyABSTRACT
Given the more or less global spread of multidrug-resistant plasmodia, structurally diverse starting points for the development of chemotherapeutic agents for the treatment of malaria are urgently needed. Thus, a series of 20 adenosine derivatives with a large lipophilic substituent in N(6)-position were prepared in order to evaluate their potential to inhibit the chloroquine resistant Plasmodium falciparum strain K1 in vitro. The rationale for synthesis of these structures was the high probability of interactions with multiple adenosine associated targets and the assumption that a large hydrophobic N(6)-(4-phenoxy)benzyl substitution should allow the molecules to diffuse across parasite membranes. Starting from readily available inosine, the new compounds were prepared as single isomers using a polymer-assisted acylation protocol enabling the straightforward isolation of the target compounds in pure form. Heterocyclic ring systems were synthesized on-bead on Kenner's safety-catch linker prior to acylation of the scaffold in solution. Most of the highly pure compounds displayed anti-plasmodial activity in the low micromolar or even submicromolar concentration range.
Subject(s)
Adenosine/analogs & derivatives , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Deoxyadenosines/chemical synthesis , Deoxyadenosines/pharmacology , Plasmodium falciparum/drug effects , Polymers/chemistry , Adenosine/chemistry , Animals , Antimalarials/chemistry , Combinatorial Chemistry Techniques/methods , Deoxyadenosines/chemistry , Structure-Activity RelationshipABSTRACT
The parallel acylation of N-{3-[4-(3-aminopropyl)piperazin-1-yl]propyl}-7-chloroquinolin-4-amine with polymer-bound carboxylic acids opened straightforward access to novel aminoquinolines with activity against Plasmodium falciparum strains in vitro. Using this amino scaffold prepared in solution and polymer-bound carboxylic, we have synthesized a series of 29 new compounds in good to excellent yield and purity. Biological evaluation included determination of the activity against a chloroquine (CQ) sensitive strain and a CQ resistant mutant. Most of the novel structures presented here displayed activity against both strains in the lower nanomolar range, four compounds showed an at least fourfold increase in the ratio of inhibition of CQ resistant to sensitive strains over CQ itself. These results suggest that this derivatization technique is a useful method to speed up structure-activity relationship studies on aminoquinolines toward improved activity versus CQ resistant strains of P. falciparum in vitro.
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Piperazines/chemical synthesis , Piperazines/pharmacology , Plasmodium falciparum/drug effects , Acylation , Animals , Chloroquine/pharmacology , Chromatography, Thin Layer , Erythrocytes/drug effects , Erythrocytes/parasitology , Humans , Indicators and Reagents , Magnetic Resonance Spectroscopy , Mass Spectrometry , Spectrometry, Mass, Electrospray Ionization , Spectroscopy, Fourier Transform Infrared , Structure-Activity RelationshipABSTRACT
[chemical reaction: see text]. Prior to detachment of compounds synthesized on sulfonamide based safety-catch linkers, the molecular anchor has to be activated. This is achieved by alkylation of the nitrogen atom of the N-acylsulfonamide using different established protocols. As an addition to the existing repertoire of activating reagents, we suggest the use of O,N,N'-trialkylisoureas. Besides the demonstration of the feasibility of these mild alkylating agents for this purpose, custom-tailored novel O,N,N'-trialkylisoureas prepared from electron-deficient alcohols are reported.
Subject(s)
Sulfonamides , Urea , Alkylation , Catalysis , Indicators and Reagents , Molecular Structure , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Urea/analogs & derivatives , Urea/chemical synthesis , Urea/chemistryABSTRACT
We have applied a fast and high-yielding method for the parallel amidation of 4-[4-(2-methoxyphenyl)piperazin-1-yl]-butylamine yielding analogs of the partial dopamine receptor agonist BP 897. Using this amino scaffold prepared in solution and polymer-bound carboxylic acid equivalents, we have synthesized a series of high affinity dopamine D(3) receptor ligands. The novel compounds were obtained in good to excellent yield and purity. Biological evaluation included determination of binding affinities at hD(2S) and hD(3) receptor subtypes. From the 22 novel structures presented here, compound 4v showed high affinity (K(i) (hD(3)) 1.6nM) and a 136-fold preference for the D(3) receptor versus that for the D(2) receptor subtype. Our results suggest that this derivatization technique is a useful method to speed up structure-activity relationships studies on dopamine receptor subtype modulators.
Subject(s)
Amides/chemistry , Amides/pharmacology , Piperazines/chemistry , Piperazines/pharmacology , Receptors, Dopamine/metabolism , Amides/chemical synthesis , Drug Evaluation, Preclinical , Molecular Structure , Piperazines/chemical synthesis , Structure-Activity RelationshipABSTRACT
The ongoing interest in ethanolamide derivatives of anti-inflammatory drugs as potential synthetic cannabinoids and mechanistic tools for the study of cannabinoid and vanilloid receptors prompted us to develop a practical gram scale synthesis for the hitherto unknown ethanolamide of fenbufen. Dehydration of fenbufen leads to intramolecular ring closure yielding bright pink crystals of the intramolecular enol ester. Reaction of this activated but stable intermediate with ethanolamine leads to the title compound in good yield and purity without the necessity to remove coupling reagents or residual activating groups, such as N, N-dialkyl ureas and fluorinated phenols.