Showing papers by "Central Drug Research Institute published in 1989"

Insulin like activity in (-) epicatechin.

Abstract: Water extract of the bark of plant ofPterocarpus marsupium Roxb is used as an antidiabetic drug in indigenous medicine in India. (−) Epicatechin, its active principle, has been found to be insulinogenic. The presentin vitro study reports some insulin like activities of (−) epicatechin. Like insulin, (−) epicatechin stimulates oxygen uptake in fat cells and tissue slices of various organs, increases glycogen content of rat diaphragm in dose-dependent manner with corresponding increase in U14-C glucose uptake, and inhibits theophylline induced lipolysis in isolated fat pads in dose-dependent manner. Experiments on competitive binding of125I-insulin and (−) epicatechin to liver cell plasma membrane indicate that insulin does not share binding site with (−) epicatechin. (−) Epicatechin at a concentration of up to 1 mM does not effect the release of glucagon from the isletsin vitro. Thus, (−) epicatechin has insulinogenic as well as insulin like properties.

Inhibition of neutrophil response by curcumin

Abstract: Blood neutrophils, when exposed to appropriate stimuli, aggregate, degranulate and generate superoxide anion. Curcumin, a non-steroidal antiinflammatory agent, modulated these functions, depending upon the kind of stimulus used. It inhibited monkey neutrophil aggregation induced by chemotactic peptide fmlp and zymosan activated plasma (ZAP) but did not affect that induced by serum treated zymosan (STZ) and arachidonic acid (AA). Generation of O 2 − radical was inhibited by curcumin, when cells were stimulated by AA, STZ and fmlp. Curcumin inhibited the release of myeloperoxidase, an azurophilic granule marker enzyme. Release of lysozyme was less susceptible to inhibition by curcumin. The results suggest that curcumin interferes with neutrophil responses to various physiological stimuli and a part of its antiinflammatory action is mediated via inhibition of neutrophil function. Inhibition of neutrophil function by curcumin appears to be mediated via calcium dependent mechanisms.

Centchroman--a non-steroidal anti-cancer agent for advanced breast cancer: phase-II study.

Abstract: Treatment with Centchroman (3,4-trans-2,2-dimethyl-3-phenyl-4-p-(beta-pyrrolidinoethoxy) phenyl-7-methoxy chroman) has been evaluated in 4 male and 75 female patients with advanced breast cancer. The overall response rate, including both male and female cases, was 40.5%. Among the female patients, the overall response rate was 38.7%. The median duration of response was 6 months. One of the 4 male patients showed a complete response and 2 showed partial responses. The responses were more marked for bone, pulmonary, soft tissue, skin and lymph-node metastases than for liver metastases.

Isothiocyanates in Heterocyclic Synthesis

Abstract: A brief introduction of the chemical structure and physico-chemical properties of various synthetic and naturally occurring isothiocyanates is presented. The different methods used to prepare alkyl, aryl, l-alkenyl, carbonyl, thiocarbonyl, l-aminoalkyl, aminophosphoryl and silyl isothiocyanates are systematically described. The use of the above isothiocyanates in the synthesis of thiazetidines, thiophenes, imidazoles, thiazoles, oxazoles, isothiazoles, oxathiolanes, dithiolanes, dioxolanes, triazoles, thiadiazoles, oxadiazoles, tetrazoles, thiatriazoles, pyridines, thiopyrans, oxazines, thiazines, pyrimidines, triazines, thiadiazines, oxadiazines, triazepines, benzimidazoles, benzothiazoles, quinazolones and various bicyclic and polyheterocyclic compounds with ring nitrogen and/or sulfur are reviewed.

Structure-activity relationship of antiestrogens: a study using triarylbutenone, benzofuran, and triarylfuran analogues as models for triarylethylenes and triarylpropenones.

Abstract: In a study of the structure-activity relationship (SAR) of antiestrogens use has been made of certain 1,2,3-triarylbutenones, of 2-arylbenzofurans carrying aryl or aroyl substituents at C3, and of 2,3,4-triarylfurans as conformationally constrained models for triarylethylene (TAE) and triarylpropenone (TAP) prototypes. The position-specific contributions of substituents to receptor affinity and to agonist-antagonist profiles were used as aids in characterizing the relative binding orientation of the prototypes. Although most compounds were found to be weak receptor ligands and poorly active in vivo, the following conclusions could be drawn about their SAR: (i) (Z)-TAPs and TAEs interact with the receptor in an analogous manner using the trans-stilbene core, with their agonist-antagonist profiles depending on the nature of other substructures. (ii) Incorporation into the benzofuran framework introduces a stereoelectronic constraint that compromises the normal binding interactions of TAE, as well as TAP, prototypes, resulting in their poor affinities and weak biological activities. (iii) (E)-TAPs can interact with the receptor through their S-cis conformation, but such a binding mode is unlikely to account for their behavior as antagonists.

Artemisinin (qinghaosu)--a new gametocytocidal drug for malaria.

Abstract: Gametocytocidal activity of artemisinin (qinghaosu) has been demonstrated against simian malaria parasite Plasmodium cynomolgi B. Colony-bred Anopheles stephensi

Radical Curative Activity of a New 8-Aminoquinoline Derivative (CDRI 80/53) against Plasmodium cynomolgi B in Monkeys

Abstract: An analogue of primaquine, N1-(3-acetyl-4-5-dihydro-2-furanyl)-N4-(6-methoxy-8-quinolinyl) 1,4-pentanediamine, CDRI Code 80/53), has been evaluated for anti-relapse activity against sporozoite induced Plasmodium cynomolgi B infection in rhesus monkeys. The compound has shown 100% curative anti-relapse activity at 1.25 mg/kg x 7 day dose schedule, thereby giving a primaquine index of 0.8. The compound is currently under Phase-I clinical trials.

Microbiological degradation of quinoline by Pseudomonas stutzeri: the coumarin pathway of quinoline catabolism

Abstract: A Gram-negative, oxidase positive, polar flagellated rod, characterised as Pseudomonas stutzeri, has been isolated from sewage by enrichment culture on quinoline. The organism utilizes quinoline as the sole source of carbon, nitrogen and energy, and liberates UV absorbing and phenolic metabolites during its growth on quinoline. 2-Hydroxyquinoline, 2,8-dihydroxyquinoline, 8-hydroxycoumarin and 2,3-dihydroxyphenylpropionic acid have been isolated as the transformation products of quinoline by this bacterium. Quinoline, 2-hydroxyquinoline, and 8-hydroxycoumarin were rapidly oxidised by quinoline-adapted cells; 2,3-dihydroxyphenylpropionic acid oxidation was also demonstrated by Warburg respirometry but 2,8-dihydroxyquinoline was not oxidised. A pathway for quinoline catabolism by P. stutzeri and the probable mechanisms for formation of 8-hydroxycoumarin are suggested.

Syntheses and bioevaluation of substituted dihydropyridines for pregnancy-interceptive activity in hamsters.

Abstract: A number of 2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-substituted-1,4- dihydropyridines were synthesized and evaluated for pregnancy-interceptive activity in mated hamsters. Out of 24 compounds, 12, 15, 21, 22, 28, and 34 caused a marked reduction in the number of implantations when administered on days 3-8 postcoitum. In an in vitro competition assay, none of the compounds exhibited noticeable binding affinity for uterine progesterone receptors. The results reported here have helped to identify new leads for developing pregnancy-interceptive agents and the active compounds do not seem to elicit their interceptive effect through receptor-mediated inhibition of progesterone action in hamster uterus.

Chemotherapeutic agents. XII [1]. Synthesis of Pyrimidines and Fused Pyrimidines as leishmanicides and herbicides†

Abstract: Various bicyclic (2, 3) and tricyclic (4, 5) heterocycles were prepared by the reaction of 1a, c with dihaloalkanes and polynitrohalobenzene separately. Electrophilic substitution on 1a–c with different alkyl halides yielded mono and dialkyl pyrimidiens (6–20). Nucleophilic substitution reactions on 18 and 21 with amine and hydrazine separately yielded 22–31, 21a, b and 41c. Reaction of 25a with ethyl ethoxymethylenecyanoacetate and chloroacetyl chloride separately provided bicyclic compounds 32 and 33. Condensation-cyclization of 25a with formic, acetic and nitrous acid separately yielded 34a, b and 35. Reaction of 26a with ethylthiocylycolate and thiourea separately provided 36a and 39. The latter was alkylated with methyl iodide to 40. An attempt to cyclize 29a and 30a with thionyl chloride provided bicyclic compounds 37a, b and an uncyclic product 38. Some of the compounds were screened for leishmanicidal and herbicidal activities and a few of them exhibited significant activity. Leishmaniasis is considered to be one of the most devastating diseases and is ominous to tropical countries. The high toxicity of leishmanicidal drugs in current use, aroused considerable interest to develop new safer and effective chemotherapeutic agents. The only drug pyrimethamine [2] is the representative of pyrimidine derivatives, known as leishmanicides but low order of activity at high dose failed to retain in the clinic. Based on our past experiences in rational designing of leishmanicidal pyrimidine analogs, incorporation of levamisole pharmacophore either in flexible or rigid forms is indispensable for potential activity [1,3] against visceral leishmaniasis. These observations induced an impetus to synthesize pyrimidine analogs as potential leishmanicides.

High performance liquid chromatographic (HPLC) determination of centchroman in human serum and application to single-dose pharmacokinetics.

Abstract: A simple and sensitive (2 ng/ml) HPLC method with fluorescence detection has been developed to measure serum concentrations of centchroman, a new nonsteroidal antifertility agent. The method was sufficiently sensitive to follow the drug over 21 days in human volunteers. Pharmacokinetic parameters of centchroman were determined after a single oral dose of 60 mg (2 × 30-mg tablets) in two healthy female volunteers. Centchroman is slowly eliminated from serum, showing a biexponential disappearance curve from serum. The terminal half-life of centchroman in the two volunteers was 168 and 175 hr, respectively.

Methemoglobin toxicity and hematological studies on malaria anti-relapse compound CDRI 80/53 in dogs

Abstract: Methemoglobin toxicities of primaquine and compound N1-(3-acetyl-4-5-dihydro-2-furanyl)-N4-(6-methoxy-8-quinolinyl) 1,4-pentanediamine, CDRI Code 80/53, have been compared in beagles. Primaquine administration at 3 mg/kg for 7 days produced significantly high (P less than 0.001) methemoglobinemia and the levels increased 10.55-fold. Compound 80/53 at 3.75 mg/kg x 7 days produced a marginal increase in methemoglobinemia (3.24-fold; P less than 0.02). The methemoglobin formed by primaquine administration was 3.65-fold (P less than 0.001) higher than that formed after administration of compound 80/53. There was no significant change in other hematological parameters and liver function tests.

Chemotherapeutic agents. XVI [1]. Synthesis of Pyrimidines and fused pyrimidines as leishmanicides

Abstract: Various mono and bicyclic pyrimidine analogs (3–15) were prepared as leishmanicides from 6-aryl-4-chloro-2-methylthiopyrimidine-5-carbonitrile (2), obtained from the halogenation of 6-aryl-3,4-dihydro-2-methylthio-4-oxopyrimidine-6-carbonitrile (1).

Comparison of antimalarial efficacy of artemisinin (qinghaosu) and arteether against Plasmodium cynomolgi B infection in monkeys.

Abstract: Arteether (30:70 mixture of alpha and beta epimers) used as injectable intramuscular preparation (in neutralized ground-nut oil) had curative action at 5 mg/kg x 3 d against blood-induced Plasmodium cynomolgi B infection in rhesus monkeys, while the curative dose of artemisinin (qinghaosu) oil suspension was 10 mg/kg x 7 d or 20 mg/kg x 3 d. Parasite clearance with arteether was achieved within 24 h. Neither arteether nor artemisinin exhibited any causal prophylactic or radical curative action up to dose levels of 20 mg/kg against sporozoite-induced P. cynomolgi B infection in rhesus monkeys.