The synthesis and antifertility evaluation of 3 analogs of pyrimethamine on male rat reproductive indices.

Side effect assessment of medicaments on fertility indices may be used as a guide in the development of male contraceptive agents. In this study, 3 analogs of pyrimethamine were synthesized and evaluated for antifertility activity on reproductive indices of male rats. Test compounds were administered in a dosage of 50 mg/kg every other day till 60 days. On the 50th day, the fertility of rats was tested. On the 60th day, the gonadosomatic index and the serum testosterone content were determined. Iso-butyloxy and tertiary-butyloxy caused 40% and 11% reduction in sperm viability, respectively. They also significantly reduced fertility indices. Consequently, iso-butyloxy can be one of the best nominees in this class of compound and a suitable candidate for assessment of mechanism involved in future research activity. To synthesize a more effective agent, increasing the lipophilicity may play a major role in the development of more potent promising male contraceptive agents.

Synthesis and assessment of fertility-regulating potential of 2-(2''-chloroacetamidobenzyl)-3-(3'-indolyl) quinoline in adult rats as a male contraceptive agent.

BACKGROUND: The purpose of this study was to investigate the fertility-regulating potential of the compound 2-(2''-chloroacetamidobenzyl)-3-(3'-indolyl) quinoline in male rats. STUDY DESIGN: Rats of proven fertility were treated with the compound by oral gavage for 1 to 8 consecutive weeks. Functional fertility, testicular, epididymal and seminal vesicular weight, epididymal sperm count and spermatogenesis were quantitated. Reproductive hormones and some biochemical parameters were measured. RESULTS: Functional fertility was reduced significantly as revealed by a fall in fertility and pregnancy rate. The weight of the reproductive organs was reduced significantly. A reduction of sperm count and number of different types of testicular cells was observed. The treatment with the compound resulted in decline of testosterone and an increase of FSH hormone levels. The compound effectively reduced testicular protein, glycogen and epididymal glyceryl phosphorylcholine. Increase in testicular alkaline phosphatase and cholesterol was also observed. Fertility and other effects were regained gradually after cessation of treatment. CONCLUSION: The results revealed from the study indicate that the compound has reversible antifertility activity and can be explored as male contraceptive agent.

Synthesis of gossypol atropisomers and derivatives and evaluation of their anti-proliferative and anti-oxidant activity.

Gossypol 1, gossypolone 2, and a series of bis 3 and half Schiff's bases 4 of gossypol were synthesised and tested for anti-proliferative and anti-oxidant activity. (-)-Gossypol (-)-1 was the most potent inhibitor of the proliferation of the HPV-16 keratinocyte cell line (using an MTT viability assay) with a GI50 of 4.8 microM. The bis Schiff's base of (-)-gossypol with L-tyrosine ethyl ester (-)-3b was the most potent inhibitor of iron/ascorbate dependent lipid peroxidation (using the thiobarbituric acid test), with an IC50 of 11.7 microM, with (-)-gossypol being the next most potent of the series, with an IC50 of 13.1 microM. The results from these initial assays suggest that gossypol, as either a racemic mixture rac-1, or the individual atropisomers (-)-1 or (+)-1, has potential for the treatment of psoriasis.

[Preparation of contraceptive pill microcapsule and its anti-fertility effect].

The main component of this pill is 2-Octadecanoic acid-4-Palmitic acid-2, 4-Pentanediyl ester separated from chloroform extract of neem oil. The microcapsules coated by the re-curdle method were fabricated with an average particle size of 100-180 microm. The morphological characteristics, incorporation efficiency, carrier reclamation efficiency of the microcapsule were investigated. Kunming mice were used in the experiment, and the anti-fertility effect of the microcapsule on the histology and apoptosis was studied by light and electron microscopy and the flow cytometry. The data obtained clearly indicated that the microcapsule could lead to the payload of medicine, the incorporation efficiency being 90%. After the microcapsules were given to the male mice orally, its anti-fertility effect came into being and could keep the mice in a state of reversible infertility for a long time. The results of histological study and flow cytometry indicate that the mechanism of its anti-fertility effect involves mainly the inhibition of sperm motility and the arrest of spermatogenic process.

Long-acting contraceptive agents: testosterone esters of unsaturated acids.

The synthesis of 13 new esters of testosterone is described, with the esterifying acids bearing acetylenic, olefinic, or polyunsaturated functions in the chain, for evaluation as long-acting androgens.

PIP: A program of the World Health Organization for developing long-acting esters of testosterone that would exhibit a more constant release rate and maintain testosterone levels in the normal range longer than testosterone enanthate found that these esters had a role in fertility, and gerontology. The synthesis of 13 new esters of testosterone is described, with the esterifying acids bearing acetylenic, olefinic or polyunsaturated functions in the chain, for evaluation as long-acting androgens. The nuclear magnetic resonance (NMR) images were recorded on a spectrometer. The samples were recorded in tubes using CDC13 as solvent. The NMR spectra were recorded with Perkin-Elmer instrument in CDC13, with tetramethylsilane as internal reference. Infrared spectra were measured on the same spectrometer. Mass spectra were also recorded. Thin-layer chromatography was performed on Merck silica gel and the spray reagent was iodine or vanillin. To a solution of testosterone the corresponding acid chloride was added yielding the pure ester after the usual work-up. E-5-methylhexa-2,4-dienoic (IXb), 5- phenylpenta-2-,4-dienoic (Xb), 5-phenyl-4-yn-pent-2-enoic (XIb), and non-4-en-6-ynoic acid (XIIb), were required for the synthesis. Esterification of testosterone with each of the first 12 unsaturated acids was performed by reaction with the corresponding acid chlorides in pyridine. Although the nona-2,3-dienoic acid ethyl ester was easily obtained, this compound could not be hydrolyzed to the acid (XIIIb). Hence, an alternative procedure was tried for the synthesis of the ester XIIIa, by reaction of bromoacetate of testosterone (XIVa) with triphenylphosphine to give the phosphorane (XVa). Reaction of this phosphorane (XVa) with 1-diazoheptan-2-one (XVI) led to the allenic ester (XIIIa).

[Synthesis and antifertility actions of gossypol derivatives and phenol aldehydes].

A series of trihydroxynaphthaldehydes, polyhydroxybiphenol-asdehydes, polyhydroxybinaphthyl aldehydes and some gossypol derivatives were synthesized for antifertility experimental studies.

Potential long-acting contraceptive agents: esters of testosterone with alkoxy- and halogeno-substituted carboxylic acids.

The chemical synthesis and physical data of several new esters of testosterone (17 beta-hydroxyandrost-4-en-3-one), which contain either a halogeno or an alkoxy substituent in the acid chain, are reported.

Potential long-acting contraceptive agents: esters and ethers of testosterone with alpha- and/or beta-chain branching.

The synthesis of ten esters and two ethers of testosterone (17 beta-hydroxyandrost-4-en-3-one) is described. All these possess some form of alpha - and/or beta - substitution in the ester/ether side-chain. The work was undertaken in order to evaluate the long-acting antifertility effect of such compounds in males.

Synthesis and evaluation of the male antifertility properties of a series of N-unsubstituted sulfamates.

A series of six aliphatic and one carbocyclic N-unsubstituted sulfamates have been synthesized and evaluated as potential male antifertility agents. Three of the aliphatic sulfamates, 1,2-ethanediyl sulfamate (1), 1,3-propanediyl sulfamate (2), and 1,4-butanediyl sulfamate (3), when administered orally to male rats caused a decrease in the number of pregnant females and/or implantation coupled with increased embryonic and fetal resorption. The compounds were prepared by treating the appropriate glycol salt with sulfamoyl chloride or by the cleavage of a tert-butylsulfamate with trifluoroacetic acid.

Phosphorus-nitrogen compounds. 21. Murine oncolytic and antifertility effect of adamantylaziridine compounds.

P,P-Bis(1-aziridinyl)-N-adamantylphosphinic amide and N,N'-bis(ethylene)-P-(1-adamantyl)phosphonic diamide were synthesized as potential anticancer and male antifertility agents. Log P values (octanol-water) of the agents were determined and compared to calculated values. Both derivatives displayed intraperitoneal murine antileukemic activity and antifertility effects when given intraperitoneally and orally.