Effects of Organoantimony(III) Compounds of Sterically Hindered Bifunctional Tetradentate Ligands on the Reproductive System of Male Rats

The antifertility activity of organoantimony(III) complexes PhSb[RC(NC6H4S)CH2(NC6H4S)CR′] {R' = CH3 (R1) and R = R' = CF3 (R2)} derived from corresponding sterically hinlered bifuinctional tetradentate ligands in the male rats was determined. The administration of compounds R1 and R2 at the dose level of 20 mg/kg. b. wt. siignificantly reduced the weights of testes and epididymides. Auxiliary glands showed a significant reduction after the treatment of compound R1 only. Treated animals showed a notable depression of spermatogenesis. The preleptotene spermatocytes were decreased by 76.19 and 47.06; the secondary spermatocytes by 87.4% and 54.87337; and the step-19 spermatids by 72.9 and 46.77% respectively, following the compound R1 and R2 treatment. Reduced sperm count and motility resulted in 100% negative fertility in both the treated groups. A significant fall in the content of various biochemical parameters of eproductive tissues was observed after R1 and R2 treatment in comparison to controls.


Introduction
A large number of antimony(Ill) compounds have been tested as bactericides[l] and fungicides [2]. The pharmacological activity of antimony compounds has developed ever since the advent of rational chemotherapy [3,4]. A number of antimony compounds have been found most effective against various diseases [5]. Phenothiazines and related compounds with the -SC6H4Nmoiety are well known to affect the hypothalamous pituitary gonadal axis and thus resulting in a delay in ovulation and menstruation in women [6]. Such type of effects were also observed in rates and dogs [7,8]. The rate of implantation was lowered and reduction in litter size have been reported by some phenothiazine derivatives [9,10]. The survey of the literature revealed that no attention has been paid to the activity of these compounds on the reproductive system of male rats. In the present investigation we are reporting the antifertility activity of organoantimony(III) complexes of sterically hindered bifunctional tetradentate ligands on the male rats.

Material and Methods
The organoantimony(III) compounds Ph3Sb[RC(NC6H4S)CH(NC6H4S)CR' where R R '= CH (R) and R R' CF (R2) were synthesised by the reaction of Ph3Sb with the corresponding ligand in 1:1 molar ratio in refluxing benzene. The structure of these compounds have been reported earlier [11]. The organic precursors used for the preparation of these complexes have been synthesised by the condensation of 2-aminothiophenol with corresponding I$-diketones (RCOCH2COR).
The route and regimen of treatment were as out lined in table I. On day 61 testes, epididymides, seminal vesicles, ventral prostate, heart, liver and adrenal were removed. The total protein, glycogen and sailic acid were measured [12][13][14]. Tissues were fixed in Bouin's fluid. Paraffin sections were made and stained with hematoxylin and eosin. The evaluation of cell population dynamics was based on the calculations made for each cell type per cross tubular sections. Various cell componenets were quantitatively analysed. The mating exposure tests of R and 1 treated male groups were performed from day 55 to day 60.
The mated females were separated to note the implantation sites on day 16th of pregnancy through leparotomy. The results were analysed using student "t" test.

Results and discussion
The administration of R at the dose level of 20 mg kg b. wt. caused the significant reduction in the body weights of treated rats. However, R did not cause any significant change in body weights. The weights of testes (P < 0.001), epididymides (p < 0.001), seminal vesicle (p < 0.01) and ventral prostate (p < 0.001) were reduced significantly following the R treatment. Whereas R treatment only reduced the weight of testes and epididymides. The number of step-I 9 spermatids were decreased by 72.9 and 46.77% following R and R administration, respectively. The population of preleptotene spermatocytes were decreased by 76.19 Y.P. Singh et al.  (table-II).  R as shown in table IV the R and R, treated rats showed significant (p < 0.001) reduction in the sperm concentration of testes and epididymides. The motility of the cauda epididymal sperm was also reduced significantly (p < 0.001). Both the treatments reduced the fertility of male rats by 100%.
Administration of R and R, for 60 days to male rats brought about a significant loss in testes weights, which is mostly related to the nubmer of spermatids and spermatozoa present in the tissue. The reduced testicular weights also indicative of wide spread damage [15]. Low cauda epididymal sperm count, presence of nonmotile spermatozoa and significant reduction in epididymal weights imply that these compounds induced infertility might be caused by several factors 16] including the oxidative phosphorylation uncoupling 17]. The reduction in sperm density and motility in cauda epididymides is of importance with regard to fertilization [18]. Reduction in number of sertoli cells following R treatment adversely affects the cell cycle kinetics and influence both spermatogonia and praleptotene spermatocytes [19]. Depletion in protein, sailic acid contents of testes and epididymides and auxiliary glands and testicular glycogen and fructose in seminal vesicle reflects the antispermatogenic effects of the R and R compounds. The results demonstrate that the compound R is more potent than compound R 2.
Spectral evidences for both the compounds suggest [11] the presence of a pentacoordinated antimony(Ill) atom in the pseudo-octahedral complexes, the geometry of which is due to the presence of lone pair of electrons is. Spectral evidences also suggest a distortion in the basal plane of the complexes.
Metal Based Drugs Vol. 7; Nr. 5,2000    It is evident from the above disussion that the antifertility activity of the compound (R) is more than the compound . It is a well known fact that the presence of halogen atom in the compound enhances its antifertility activity [20,21]. But in the present study the hexafluoro derivative l was found to be less active than the non-fluorirated derivative. It might be possible that compound R may have a positive effect on male reproductive system. This may be verified by carrying out the toxicological effect of both the compounds. The study is in progress and the results will be published in due course of time.