ABSTRACT
Twenty-six simple isoquinolines and 21 benzylisoquinolines were tested for antimicrobial, antimalarial, cytotoxic, and anti-HIV activities. Some simple isoquinoline alkaloids were significantly active in each assay, and may be useful as lead compounds for developing potential chemotherapeutic agents. These compounds include 13 (antimicrobial), 25, 26, and 42 (antimalarial), 13 and 25 (cytotoxic), and 28 and 29 (anti-HIV). A quaternary nitrogen atom of isoquinolium or dihydroisoquinolinium type may contribute to enhanced potency in the first three types of activities. In contrast, anti-HIV activity was found with tetrahydroisoquinoline and 6,7-dihydroxyisoquinolium salts.
Subject(s)
Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Isoquinolines/pharmacology , Alkaloids/chemical synthesis , Alkaloids/chemistry , Alkaloids/pharmacology , Animals , Anti-Bacterial Agents , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Anti-Infective Agents/chemistry , Antimalarials/chemical synthesis , Antimalarials/chemistry , Antimalarials/pharmacology , Antineoplastic Agents/chemistry , Candida albicans/drug effects , Cell Division/drug effects , Crystallization , Drug Evaluation, Preclinical , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , HIV-1/drug effects , Humans , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Magnetic Resonance Spectroscopy , Mice , Microbial Sensitivity Tests , Plasmodium falciparum/drug effects , Structure-Activity Relationship , Tumor Cells, Cultured/drug effectsABSTRACT
CsOH- or Ag(2)O-mediated cycloalkylation of (alkylidene)bisperoxides 3 and 1,n-dihaloalkanes (n = 3-8) provided the corresponding medium-sized 1,2,4,5-tetraoxacycloalkanes 4-8 in moderate yields. Subsequent evaluation of the antimalarial activity of the cyclic peroxides 4-8 in vitro and in vivo revealed that 1,2,6,7-tetraoxaspiro[7.11]nonadecane 4a has considerable potential as a new, inexpensive, and potent antimalarial drug.
Subject(s)
Antimalarials/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemical synthesis , Spiro Compounds/chemical synthesis , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Cesium , Cyclization , Drug Evaluation, Preclinical , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacology , Hydroxides , Malaria/drug therapy , Malaria/parasitology , Mice , Oxides , Plasmodium berghei , Plasmodium falciparum/drug effects , Silver Compounds , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
The antimalarial activity of the O-acylated bruceolide derivative, 3,15-di-O-acetylbruceolide, was evaluated against Plasmodium berghei in vivo. The concentration of 3,15-di-O-acetylbruceolide required for 50% suppression (ED50) of P. berghei in mice was 0.46 +/- 0.06 mg/kg/day, whereas bruceolide was only half as effective as 3,15-di-O-acetylbruceolide. Two antimalarial drugs used clinically, chloroquine and artemisinin, demonstrated only low activity corresponding to 1/4 and 1/12 of the ED50 value of 3,15-di-O-acetylbruceolide, respectively. These results may be helpful in the design of better chemotherapeutic bruceolides against falciparum malaria.
Subject(s)
Antimalarials/therapeutic use , Artemisinins , Carbolines/therapeutic use , Malaria/drug therapy , Plasmodium berghei/drug effects , Pyridones/therapeutic use , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Carbolines/chemistry , Carbolines/pharmacology , Chloroquine/pharmacology , Chloroquine/therapeutic use , Dose-Response Relationship, Drug , Male , Mice , Mice, Inbred ICR , Pyridones/chemistry , Pyridones/pharmacology , Random Allocation , Sesquiterpenes/pharmacology , Sesquiterpenes/therapeutic useABSTRACT
Febrifugine (1) and isofebrifugine (2), isolated from the roots of Dichroa febrifuga Lour. (Chinese name: Cháng Shan), are active principles against malaria. Adducts of 1 and 2 with acetone, Df-1 (3) and Df-2 (4), respectively, were obtained using silica gel and acetone. They showed high activity against P. falciparum malaria in vitro. Compound 3 was found to be equally effective against P. berghei in vivo as the clinically used drug chloroquine, whereas 4 showed only 1/24 of the activity of 3. Metabolism studies of these compounds revealed that compound 4 is readily metabolized in mouse liver. Accordingly, the dose of 4 must be higher than that of 3 to attain blood levels sufficient for a favorable therapeutic effect.
Subject(s)
Antimalarials/chemical synthesis , Drugs, Chinese Herbal/pharmacology , Plasmodium berghei , Plasmodium falciparum/drug effects , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Quinolizines/chemical synthesis , Animals , Antimalarials/chemistry , Antimalarials/isolation & purification , Antimalarials/pharmacology , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/isolation & purification , Malaria/drug therapy , Male , Mice , Mice, Inbred ICR , Models, Molecular , Molecular Conformation , Piperidines , Quinazolines/chemistry , Quinazolines/isolation & purification , Quinazolinones , Quinolizines/chemistry , Quinolizines/pharmacologyABSTRACT
Cycloprodigiosin hydrochloride (cPrG*HCl) is a stable fluorescent red pigment obtained from the marine bacterium Pseudoalteromonas denitrificans. It was found that the compound was incorporated into Plasmodium falciparum cells upon incubation and exhibited a potent antimalarial activity with the concentration required for 50% of the activity being 11 nM, which is stronger than that of chloroquine, a well-known antimalarial agent. The compound did not affect growth rate of mammalian cells. Antimalarial activity of cPrG*HCl was also observed in vivo. These results indicate that cPrG*HCl is a potent antimalarial drug.
Subject(s)
Antimalarials/pharmacology , Gram-Negative Aerobic Bacteria/chemistry , Indoles/pharmacology , Malaria/drug therapy , Plasmodium falciparum/drug effects , Pyrroles/pharmacology , Animals , Antimalarials/isolation & purification , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , In Vitro Techniques , Indoles/isolation & purification , Male , Mice , Mice, Inbred ICR , Pyrroles/isolation & purificationABSTRACT
We have developed DNA diagnosis using Universal probe system for the rapid detection of Plasmodium falciparum parasite in blood. We chose the DHFR-TS (dihydrofolate reductase-thymidylate synthase) gene as target for detection which are the junction part (410 bp) of and the DHFR part (790 bp). In the parasite, there is only one copy of target sequence, therefore, the target sequences were amplified by PCR (polymerase chain reaction) to increase the sensitivity. Our hybridization method consists of two probes; a primary probe prepared from a chimeric phage-plasmid vector (pUCf1) containing sequence complementary to the target, and a biotin-labeled secondary probe complementary to a portion of the primary probe, which is detected by the BCIP/NBT method. We showed that the 410 bp was more sensitive than the 790 bp as a target of P. falciparum, and the limit of detection was 10(3) parasites in 1 ml human blood using 410 bp junction part. We also constructed double PCR systems using junction part of DHFR-TS gene. By amplification of the 410 bp of the junction part and reamplification of 228 bp of inside sequence of the 410 bp, as little as 10 parasites in 10 microliters human blood was sufficient for specific detection.
Subject(s)
DNA, Protozoan/blood , Malaria, Falciparum/diagnosis , Plasmodium falciparum/isolation & purification , Polymerase Chain Reaction/methods , Animals , Base Sequence , DNA Probes , Humans , Malaria, Falciparum/parasitology , Molecular Sequence Data , Plasmodium falciparum/enzymology , Plasmodium falciparum/genetics , Tetrahydrofolate Dehydrogenase/genetics , Thymidylate Synthase/geneticsABSTRACT
Many nucleoside analogs were screened for anti-protozoa activity on Leishmania tropica in an in vitro culture system. 3'-Deoxyinosine and several tubercidin derivatives were found to be potent inhibitors for growth of the promastigote form of L. tropica. EC50 value of 3'-deoxyinosine was 4.43 X 10(-7)M. This compound was remarkably less toxic towards mouse mammary tumor FM3A cells (EC50, 1.25 X 10(-4) M). 3'-Deoxyinosine is metabolized by Leishmania promastigote to give 3'-deoxyinosine-5'-monophosphate, 3'-deoxy-adenosine(cordycepin)-5'-mono, di-, and triphosphates. This means that Leishmania can aminate the 6-position of 3'-deoxyinosine-5'-monophosphate, thereby converting it into a highly toxic compound.