ABSTRACT
Based on the indoloquinoline alkaloids cryptolepine (1), neocryptolepine (2), isocryptolepine (3) and isoneocryptolepine (4), used as lead compounds for new antimalarial agents, a series of tricyclic and bicyclic analogues, including carbolines, azaindoles, pyrroloquinolines and pyrroloisoquinolines was synthesized and biologically evaluated. None of the bicyclic compounds was significantly active against the chloroquine-resistant strain Plasmodium falciparum K1, in contrast to the tricyclic derivatives. The tricyclic compound 2-methyl-2H-pyrido[3,4-b]indole (9), or 2-methyl-beta-carboline, showed the best in vitro activity, with an IC(50) value of 0.45 microM against P. falciparum K1, without apparent cytotoxicity against L6 cells (SI>1000). However, this compound was not active in the Plasmodium berghei mouse model. Structure-activity relationships are discussed and compared with related naturally occurring compounds.
Subject(s)
Antimalarials/pharmacology , Antineoplastic Agents/pharmacology , Indole Alkaloids/chemistry , Indole Alkaloids/pharmacology , Animals , Mice , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Structure-Activity RelationshipABSTRACT
A series of chloro- and aminoalkylamino-substituted neocryptolepine (5-methyl-5H-indolo[2,3-b]quinoline) derivatives were synthesized and evaluated as antiplasmodial agents. The evaluation also included cytotoxicity (MRC5 cells), inhibition of beta-hematin formation, and DNA interactions (DNA-methyl green assay). Introduction of aminoalkylamino chains increased the antiplasmodial activity of the neocryptolepine core substantially. The most efficient compounds showed antiplasmodial activities in the nanomolar range. N(1),N(1)-Diethyl-N(4)-(5-methyl-5H-indolo[2,3-b]quinolin-8-yl)pentane-1,4-diamine 11c showed an IC(50) of 0.01 microM and a selectivity index of 1800.
Subject(s)
Alkaloids/chemical synthesis , Alkaloids/pharmacology , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Drug Design , Plasmodium falciparum/drug effects , Quinolines/chemical synthesis , Quinolines/pharmacology , Alkaloids/chemistry , Alkaloids/metabolism , Animals , Antimalarials/chemistry , Antimalarials/metabolism , DNA, Protozoan/metabolism , Mice , Quinolines/chemistry , Quinolines/metabolismABSTRACT
Indoloquinoline alkaloids represent an important class of antimalarial, antibacterial and antiviral compounds. They have been shown to bind to DNA via intercalation preferentially at GC-rich sequences containing nonalternating CC sites. The stability of complexes formed with biological macromolecules depends on noncovalent binding. In the present study, the ability of indoloquinolines to form intermolecular interactions with solvents was investigated by using NMR spectroscopy and density functional theory (DFT) (B3LYP/6-31G**) calculations. NMR data measured for indoloquinoline bases and the corresponding hydrochlorides are discussed in relation to the structure. DFT calculations of shielding constants in vacuo and in solution allowed the investigation of the influence of the environment on the NMR parameters. Calculations incorporating solvent effects indicated significant changes in the anisotropy of the electron distribution, reflected in the span of the chemical shielding tensor (Omega = sigma11 - sigma33). Solvent effects on the span of the 13C and 15N shielding tensor depended on the type of atom and the data indicated a significant influence of solute-solvent interactions.
Subject(s)
Alkaloids/chemistry , Indoles/chemistry , Magnetic Resonance Spectroscopy , Models, Theoretical , Quinolines/chemistry , Solvents/chemistry , Carbon Isotopes , Nitrogen IsotopesABSTRACT
A set of regioisomeric 2-substituted pyridazin-3(2H)-ones containing a 3-oxo-3-phenylprop-1-en-1-yl fragment at either position 4, 5 or 6 and 2-substituted pyridazin-3(2H)-ones containing the same fragment both at positions 4 and 5 have been synthesized and evaluated as antiplatelet agents. The study allows the identification of a new highly potent platelet aggregation inhibitor (4c).
Subject(s)
Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacology , Pyridazines/chemistry , Pyridazines/pharmacology , Drug Design , Platelet Aggregation Inhibitors/chemical synthesis , Pyridazines/chemical synthesis , Structure-Activity RelationshipABSTRACT
As part of the optimization process of the lead compound I a focussed library of diversely substituted pyridazin-3(2H)-ones containing a 3-oxo-3-phenylprop-1-en-1-yl or 3-phenylprop-2-enoyl fragment at position 5 has been obtained and evaluated as antiplatelet agents. The structural modification at positions 2, 6 and 4 of the heterocyclic moiety allowed us to obtain preliminary information on the structure-activity relationship in this family.
Subject(s)
Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation/drug effects , Pyridazines/chemical synthesis , Pyridazines/pharmacology , Molecular Structure , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacology , Pyridazines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The antiprotozoal activities of three naturally occurring isomeric indoloquinoline alkaloids, i.e., cryptolepine (1), neocryptolepine (2), and isocryptolepine (3), and two dimeric indoloquinoline alkaloids, cryptoquindoline (6) and biscryptolepine (7), originally obtained from the plant Cryptolepis sanguinolenta, were compared with those of a new synthetic indoloquinoline isomer, isoneocryptolepine (4), and a quaternary derivative, N-methyl-isocryptolepinium iodide (5). The latter compounds showed a high antiplasmodial activity against the chloroquine-resistant Plasmodium falciparum strain K1 (IC50 of 0.23 +/- 0.04 and 0.017 +/- 0.004 microM, respectively), while the cytotoxicity (L6 cells) was 4.32 +/- 0.04 and 12.7 +/- 2.0 microM, respectively. Isoneocryptolepine (4) was found to act as an inhibitor of beta-hematin formation and as a DNA-intercalating agent.
Subject(s)
Alkaloids/chemical synthesis , Alkaloids/pharmacology , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Animals , Apocynaceae/chemistry , Indole Alkaloids , Indoles/pharmacology , Molecular Structure , Plasmodium falciparum/drug effects , Structure-Activity RelationshipABSTRACT
The synthesis of four novel compounds, (i) [(11-{[2-(3-nitrophenyl)-4-oxo-1,3-thiazolidin-3-yl]amino}-11-oxoundecyl)sulfanyl]acetic acid (4), (ii) N-[5-methyl-2-(3-nitrophenyl)-4-oxo-1,3-thiazolidin-3-yl]undec-10-enamide (5), (iii) 2-[(11-{[5-methyl-2-(3-nitrophenyl)-4-oxo-1,3-thiazolidin-3-yl]amino}-11-oxoundecyl)sulfanyl]propanoic acid (6) and (iv) 3-[(11-{[2-(3-nitrophenyl)-4-oxo-1,3-thiazinan-3-yl]amino}-11-oxoundecenyl) sulfanyl]propanoic acid (8) from 10-undecenoic acid hydrazide (1) via m-nitrobenzaldehyde-10-undecenohydrazone (2) using mercaptoacetic acid in (i), 2-mercaptopropionic acid in (ii and iii) and 3-mercaptopropionic acid in (iv) is described. The uncyclized products, ({11-[(2E)-2-(3-nitrobenzylidene)hydrazino]-11-oxo-undecyl}sulfanyl)acetic acid (3) and 3-({11-[(2E)-2-(3-nitrobenzylidene)hydrazino]-11-oxoundecyl}sulfanyl)propanoic acid (7) are also obtained in (i) and (iv), respectively. The hydrazones (2), (3) and (7) exist in two conformers as synperiplanar and antiperiplanar. Structural assignment, stereochemistry and biological assays are discussed.
Subject(s)
Acetates/chemical synthesis , Anti-Infective Agents/chemical synthesis , Antineoplastic Agents/chemical synthesis , Hydrazines/chemical synthesis , Hydrazones/chemical synthesis , Nitrobenzenes/chemical synthesis , Thiazoles/chemical synthesis , Acetates/pharmacology , Anti-Infective Agents/pharmacology , Antineoplastic Agents/pharmacology , Bacteria/drug effects , Biological Assay , Drug Screening Assays, Antitumor , Humans , Hydrazines/pharmacology , Hydrazones/pharmacology , Microbial Sensitivity Tests , Models, Chemical , Nitrobenzenes/pharmacology , Stereoisomerism , Sulfur Compounds , Thiazoles/pharmacology , Tumor Cells, CulturedABSTRACT
A series of synthetic dihydrobenzofuran lignans and related benzofurans were evaluated for their cytotoxicity in a screening panel consisting of various human tumour cell lines, and for their antiprotozoal activity against L. donovani (axenic amastigotes), chloroquine resistant Plasmodium falciparum (strain K1), Trypanosoma brucei rhodesiense and T. cruzi, and for cytotoxicity on L6 cells. No promising cytotoxicities against human tumour cell lines were observed for newly synthesised compounds, but the dimerisation product of some lipophylic esters of caffeic acid, such as compound 2g, showed a high activity against chloroquine-resistant P. falciparum (strain K1) (IC50 0.43 microg/mL) and L. donovani (axenic amastigotes) (IC50 0.12 microg/mL), which was confirmed in an infected macrophage assay (IC50 0.19 microg/mL). QSAR models for the cytotoxic and antileishmanial activity were generated using Quasar receptor surface modelling.
Subject(s)
Antiprotozoal Agents/pharmacology , Benzofurans/pharmacology , Leishmania/drug effects , Lignans/pharmacology , Animals , Antiprotozoal Agents/chemistry , Benzofurans/chemistry , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Lignans/chemistry , Quantitative Structure-Activity RelationshipABSTRACT
Neocryptolepine, a minor alkaloid of Cryptolepis sanguinolenta, was investigated as a lead for new antiplasmodial agents, because of its lower cytotoxicity than cryptolepine, the major alkaloid. Synthetic 2- or 3-substituted neocryptolepine derivatives were evaluated for their biological activity. In addition to the antiplasmodial activity (Plasmodium falciparum chloroquine-sensitive and -resistant) also the cytotoxicity (MRC-5 cells) was determined. Several compounds such as 2-bromoneocryptolepine showing higher and more selective antiplasmodial activity than neocryptolepine were obtained. Several functional assays and in vitro tests were used to obtain additional information on the mechanism of action, i.e., the beta-haematin formation inhibitory assay (detoxification of haem) and the DNA-methylgreen displacement assay (interaction with DNA). It could be demonstrated that the 2- or 3-substituted neocryptolepine derivatives investigated here have about the same potency to inhibit the beta-haematin formation as chloroquine, indicating that inhibition of haemozoin formation makes at least an important contribution to their antiplasmodial activity, although their in vitro antiplasmodial activity is still less than chloroquine.
Subject(s)
Alkaloids/pharmacology , Antimalarials/pharmacology , DNA/metabolism , Hemeproteins/antagonists & inhibitors , Plasmodium falciparum/drug effects , Quinolines/pharmacology , Alkaloids/chemistry , Alkaloids/toxicity , Animals , Antimalarials/chemistry , Antimalarials/toxicity , Cell Line , Cryptolepis , Humans , Indole Alkaloids , Indoles/pharmacology , Quinolines/chemistry , Quinolines/toxicityABSTRACT
A new strategy for the synthesis of the title compounds via a regio- and chemoselective one-pot inter- and intramolecular Buchwald-Hartwig amination of 2-chloro-3-iodopyridine with aminoazines and -diazines is reported.
Subject(s)
Aza Compounds/chemical synthesis , Imidazoles/chemical synthesis , Organometallic Compounds/chemistry , Palladium/chemistry , Pyridines/chemical synthesis , Amidines/chemistry , Amination , Catalysis , Imidazoles/chemistry , Molecular StructureABSTRACT
Evidence for an interphase deprotonation of Pd(II)-amine complexes with weak carbonate base has been gained for the first time. When a rate-limiting deprotonation step is involved in the catalytic cycle, controlling the structure (shape and size of the particles) and/or molar excess of the carbonate base used can significantly increase the reaction rate of Buchwald-Hartwig aminations. By taking such a "base effect" into account a general protocol for the intermolecular amination of aryl iodides with all types of amines has been developed based on a standard Pd-BINAP catalyst, using cesium carbonate as the base.
ABSTRACT
On the basis of the original lead neocryptolepine or 5-methyl-5H-indolo[2,3-b]quinoline, an alkaloid from Cryptolepis sanguinolenta, derivatives were prepared using a biradical cyclization methodology. Starting from easily accessible educts, this approach allowed the synthesis of hitherto unknown compounds with a varied substitution pattern. As a result of steric hindrance, preferential formation of the 3-substituted isomers over the 1-substituted isomers was observed when cyclizing N-(3-substituted-phenyl)-N'-[2-(2-trimethylsilylethynyl)phenyl]carbodiimides. All compounds were evaluated for their activity against chloroquine-sensitive as well as chloroquine-resistant Plasmodium falciparum strains, for their activity against Trypanosoma brucei and T. cruzi, and for their cytotoxicity on human MRC-5 cells. Mechanisms of action were investigated by testing heme complexation using ESI-MS, inhibition of beta-hematin formation, DNA interactions (DNA-methyl green assay and linear dichroism), and inhibition of human topoisomerase II. Neocryptolepine derivatives with a higher antiplasmodial activity and a lower cytotoxicity than the original lead have been obtained. This selective antiplasmodial activity was associated with inhibition of beta-hematin formation. 2-Bromoneocryptolepine was the most selective compound with an IC(50) value against chloroquine-resistant P. falciparum of 4.0 microM in the absence of cytotoxicity (IC(50) > 32 microM). Although cryptolepine, a known lead for antimalarials also originally isolated from Cryptolepis sanguinolenta, was more active (IC(50) = 2.0 microM), 2-bromoneocryptolepine showed a low affinity for DNA and no inhibition of human topoisomerase II, in contrast to cryptolepine. Although some neocryptolepine derivatives showed a higher antiplasmodial activity than 2-bromocryptolepine, these compounds also showed a higher affinity for DNA and/or a more pronounced cytotoxicity. Therefore, 2-bromoneocryptolepine is considered as the most promising lead from the present work for new antimalarial agents. In addition, 2-bromo-, 2-nitro-, and 2-methoxy-9-cyanoneocryptolepine exhibited antitrypanosomal activity in the micromolar range in the absence of obvious cytotoxicity.
Subject(s)
Alkaloids/chemical synthesis , Antimalarials/chemical synthesis , Quinolines/chemical synthesis , Trypanocidal Agents/chemical synthesis , Alkaloids/pharmacology , Alkaloids/toxicity , Animals , Antimalarials/pharmacology , Antimalarials/toxicity , Cell Line , DNA/chemistry , Heme/chemistry , Hemin/chemistry , Humans , Intercalating Agents/chemical synthesis , Intercalating Agents/pharmacology , Intercalating Agents/toxicity , Plasmodium falciparum/drug effects , Polymers , Quinolines/pharmacology , Quinolines/toxicity , Spectrometry, Mass, Electrospray Ionization , Structure-Activity Relationship , Topoisomerase II Inhibitors , Trypanocidal Agents/pharmacology , Trypanocidal Agents/toxicity , Trypanosoma brucei brucei/drug effects , Trypanosoma cruzi/drug effectsABSTRACT
A series of synthetic dihydrobenzofuran lignans, obtained by biomimetic oxidative dimerization of caffeic or ferulic acid methyl ester followed by derivatization reactions, was tested for its antiangiogenic activity in the CAM (chorioallantoic membrane) assay. The dimerization product of caffeic acid methyl ester (2a) (methyl (E)-3-[2-(3,4-dihydroxyphenyl)-7-hydroxy-3-methoxycarbonyl-2,3-dihydro-1-benzofuran-5-yl]prop-2-enoate) showed a pronounced antiangiogenic activity, especially the 2R,3R-enantiomer.
Subject(s)
Angiogenesis Inhibitors/isolation & purification , Benzofurans/chemical synthesis , Lignans/chemical synthesis , Propionates/chemical synthesis , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Benzofurans/chemistry , Benzofurans/pharmacology , Caffeic Acids/chemistry , Catalysis , Chorion/drug effects , Chromatography, High Pressure Liquid , Lignans/chemistry , Lignans/pharmacology , Magnetic Resonance Spectroscopy , Molecular Structure , Propionates/chemistry , Propionates/pharmacology , StereoisomerismABSTRACT
The synthesis of 2-(2,2-bis(4-chlorophenyl)ethyl]-2-(4-chlorophenyl)-thiazolidin-4-one (3) from p,p'-dichlorochalcone (1) via 1,3,3-tris(4-chlorophenyl)-propan-1-one (2) using thioglycollic acid in the presence of ammonium carbonate is described. Structural assignment, stereochemistry and biological assay are discussed.