Manju Seth

Pregnancy interceptive efficacy and biological profile of 3-amino-6,7-dimethoxy-1H-pyrazolo [3,4-b] quinoline (compound 85/83) in rodents

Administration of compound 85/83 during the peri- and post-implantation period intercepted pregnancy in hamster and guinea pig by parenteral route and in hamster by oral route also. The m.e.d. for hamster and guinea pig was 10 and 20 mg/kg, respectively; lower doses were less effective. Restricting the administration to early post-implantation schedule interrupted pregnancy partially in both species. The compound was, however, ineffective in rat and in the pre-implantation schedule (days 1-4 post-coitum) in hamster. When tested in vitro on growing trophoblasts at 13.8 x 10(-5) M concentration, it prevented growth and caused degeneration of the cells within 24 h; lower concentration (9.2 x 10(-5) M) was less effective. The compound was found to be devoid of estrogenic, antiestrogenic, progestational and antiprogestational properties in conventional bioassays. In hormone competition assays, its relative binding affinity (RBA) to estrogen receptor was negligible (0.002% of estradiol-17 beta), while for uterine cytosol progesterone receptors in rabbit and hamster was 0.06 and 0.08% of progesterone, respectively. The compound 85/83 appears to intercept pregnancy by interfering with development of trophoblast cells.

Contraceptive and hormonal properties of a new 1,4-dihydro-2-oxoquinoline derivative (compound 84–182) in rodents and rhesus monkeys

Compound 84-182 prevented pregnancy when administered subcutaneously at 10 mg/kg dose on days 3-8 post-coitum in hamsters and on days 6-10 post-coitum in guinea pigs. At lower doses, while in hamsters there was a marked reduction in implantation number, majority of implantations in guinea pigs showed signs of resorption. The compound was ineffective when administered at 10 mg/kg dose on days 1-3 or 6-7 post-coitum in hamsters and on days 1-5 or 4-8 post-coitum in rats. In rhesus monkeys, treatment with the compound at 5 and 10 mg/kg doses on days 16-21 of the menstrual cycle induced frank vaginal bleeding between days 21 and 24. Treatment on days 21-30 or after confirmation of pregnancy on days 32-36 was ineffective. In conventional bioassays, the compound was devoid of any estrogenic, antiestrogenic, progestational, antiprogestational, androgenic or antiandrogenic properties at the contraceptive dose. In competitive protein binding assay, the compound showed relative binding affinity (RBA) of less than 0.1% and 0.28% of progesterone, respectively, for rabbit and hamster uterine cytosol progesterone receptors. Its RBA for rat uterine cytosol estrogen receptors was less than 0.1% of estradiol-17 beta.

Chirality and future drug design

Design and development of a new drug involves the integration of inputs from a number of diverse disciplines: medicinal chemistry, biochemistry, molecular biology, pharmacology, pharmacokinetics, toxicology, clinical medicine and chemical engineering. A new dimension has recently been added to drug design as a consequence of the growing awareness of the important role of the asymmetric centre in the case of chiral drugs. Studies on the relationship between the stereochemistry and biological activity of a wide variety of bioactive molecules have established that a particular biological response is evoked by a definite stereochemistry. Hence knowledge of the absolute stereochemistry of the asymmetric centre(s) is a pre-requisite for the development of a chiral compound as a drug. The question that arises is why this current concern with chirality. Ariens [1–14] has discussed the problem in great detail. However, it will be sufficient to mention only the salient points here. Often only one isomer in a racemate is therapeutically active, while the other may be inactive or exhibit some other bioactivity. Thus the racemate drug can be considered as only 50% “pure” which is a matter of concern for drug regulatory agencies. The fact that many racemate drugs such as atenolol, ibuprofen, lorezepam, terbutline, warfarin, metoprolol and chlorthalidone are widely used adds to this concern and the magnitude of problem becomes greater if the therapeutically inactive isomer (so-called 50% impurity) possesses significant undesired bioactivity.

Recent developments in 8-aminoquinoline antimalarials

Malaria is an old scourge of mankind and mention of the disease is found in ancient writings in India, Egypt and China [1]. The clinical symptoms of this disease were described by Hippocrates 400 years before the Christian era [1]. Human population affected by malaria is alarmingly large in tropical regions although in the past the disease was also prevalent in temperate regions [1]. The respite from this disease after World War II, due to the success in the control of the vector mosquitoes and development of new antimalarials, was, however, short lived and malaria has staged a come back in recent years. Only two decades back WHO had stated The clinicians have at their disposal a complete series of effective drugs for the treatment of all stages of this disease’ [2] but in 1971 the same organization considered malaria eradication as a difficult problem both technically and politically [3] and commented ‘Thus there is no avoiding the conclusion that malaria will be with us for quite sometime. In order to cope more efficiently with this world-wide problem, much more research is required’ [4]. It would, therefore, be pertinent to analyse the main causes of this set-back. The principal reason is undoubtedly the appearance of drug-resistance in malarial parasites. Resistance to all the currently available drugs is a reality; even the age-old remedy, quinine, has the same limitations as the synthetic drugs.

Present status of Leishmaniasis

Leishmaniasis has been identified by WHO as a major and increasing public health problem. Its exact global incidence is not known but the estimated figure varies between 400 000 to 12 million cases per annum [1, 2]. Diverse species of genus Leishmania are responsible for this group of diseases but sandfly either of the genus Phlebotomus (old world) or Lutzomyia (new world) is invariably the vector. All leishmanial parasites are obligate intracellular organisms found within the macrophage phagolysosomes of the vertebrate host [3, 4]. A comprehensive review on leishmaniasis [5] was published in 1974 and the present review deals with the various developments made during the last one and a half decades in this field. The major thrust of this review is directed towards detailed understanding of the biological, biochemical and immunological aspects of the disease and also the mode of action of available antileishmanial agents.

REGIOSELECTIVE REACTIONS OF 1,2-DEHYDROPROGESTERONE : SYNTHESES OF PREGNANE DERIVATIVES AS POSSIBLE CONTRAGESTATIONAL AGENTS

A few pregnane derivatives were synthesized from 1,2-dehydroprogesterone (1). Ring A of 1,2-dehydroprogesterone was aromatized without affecting C-20, and the resulting acetoxy compound (2) after hydrolysis yielded 1-hydroxy-4-methyl-19-norpregna-1,3,5(10)-trien-20-one (3). Reactions of the phenol (3) with alkyl halides yielded the ethers 6a-6b and 7. Opening of the oxirane ring in 7 with secondary amines furnished the aminoalcohols 8a-8b. Friedelcrafts reaction of 3 with maleic anhydride and chloracetyl chloride led to the formation of 9 and 10, respectively. Base-catalyzed ring closure of 10 yielded 1-acetyl-12a-methyl-8-oxo-5[H]-1,2,3,3a,3b,4,8,9,10b,11,12, 12a-dodecahydrocyclopenta (7,8)-phenanthro (3,4-b) furan (11), which reacted with aromatic aldehydes regioselectively to furnish 12a-12b. Reaction of 1 with triethylorthoformate in the presence of boron trifluoride etherate involved the participation of C-21, and the carbonyl at C-3 remained unaffected. The product 13 was identified as 21-[2-hydroxyvinyl]-21-norpregna-1,4-diene-3,20-dione. Reductive amination with sodium cyanoborohydride in the presence of ammonium acetate did not attack ring A and smoothly furnished the amine 14 which, on reaction with succinic anhydride, gave 20-succinamylpregna-1,4-dien-3-one (15).