Changes of CaM-CaMK-CREB signaling pathway and related neuron factors in hippocampus of rats after sevoflurane and propofol administration.

OBJECTIVE: To investigate the changes of CaM-CaMK-CREB signaling pathway and related neuron factors in hippocampus of rats after sevoflurane and propofol administration. MATERIALS AND METHODS: A total of 90 SD rats, half male and half female, were selected. They were randomized into anesthesia group (AG) and control group (CG), in which 30 rats under propofol anesthesia in the AG were included in group A, 30 rats under sevoflurane anesthesia were included in group B, and 30 rats under mixed ventilation of air and oxygen were included in the CG. Before (10 rats were killed in each group) and at the end of anesthesia (2 weeks of anesthesia and 7 days of Morris water maze test), rats were respectively killed and then an appropriate amount of hippocampus was separated. Human tumor necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF), calmodulin (CaM), calmodulin-dependent kinase Ⅱ a (CaMK II a), NMDA receptor 2B (NR2B), cysteine aspartate specific protease-3 mRNA (Caspase-3mRNA) and protein contents were detected. RESULTS: The latency of rats in group A and group B, as well as their times of crossing the original platform on 1, 4, and 7d were markedly higher than those of the CG, and those in group B were markedly lower than those in group A (p<0.001). The total distance of rats in group A and group B on 1, 4, and 7d was significantly higher than that of the CG, and that in group B was dramatically lower than that in group A (p<0.001). The speed of rats in the three groups ranged from 1d to 7d, and there was no significant difference at different time points (p>0.05). At the end of anesthesia, the expression levels of CaM mRNA and protein in hippocampus of rats in group A and group B were remarkably higher than those of the CG, and those of CaMK II a mRNA and protein were remarkably lower than those of the CG; the CaM mRNA and protein expression levels in hippocampus of group A were significantly higher than those of group B, and those of CaMK IL a mRNA and protein were significantly lower than those of group B (p<0.001). Simultaneously, the expression levels of NR2BmRNA, Caspase-3mRNA and protein in hippocampus of group A and group B were substantially higher than those of the CG, and those in group B were substantially lower than those in group A (p<0.001). What's more, the TNF-a and VEGF expression levels in hippocampus of group A and B were markedly higher than those of the CG, and those in group B were dramatically lower than those of group A (p<0.001). CONCLUSIONS: Sevoflurane anesthesia on the CaM-CaMK-CREB signaling pathway and learning and memory function of rats is less volatile, which does better in safeguarding stability.

[Effect of a new ROCK inhibitor thiazovivin on the morphology and function of human corneal endothelial cells].

OBJECTIVE: To evaluate the effect of thiazovivin, a novel ROCK inhibitor, on the morphology and function of human corneal endothelial cells(HCECs). METHODS: The primary HCECs were identified by light microscopy and immunofluorescence staining of neuron-specific enolase. To screen the optimal concentration and action time of thiazovivin for maintaining the morphology and function of primary HCECs, Na (+)/K (+)-ATPase and N-cadherin were chosen as indicators, and the morphology and function of HCECs in various concentrations(0 µmol/L, 2 µmol/L, 4 µmol/L, and 6 µmol/L)for different durations(24 h and 48 h)were examined by immunofluorescence experiments. The effect of thiazovivin on the expression of ROCK was investigated by immunofluorescence and Western blot. RESULTS: The primary HCECs cultured were hexagonal, closely packed, homogeneously and obviously stained by neuron-specific enolase. The immunofluorescence staining of Na(+)/K(+)-ATPase showed that when the primary HCECs cultured with various concentrations of thiazovivin(0, 2, 4, 6 µmol/L)for 24 h, the fluorescence were obvious, and the average absorbance values(A)were 1.27±0.08, 3.72±0.17, 21.07±4.67, 3.69±0.34, respectively. And the immunofluorescence staining of N-cadherin revealed that when the primary HCECs treated with 4 µmol/L thiazovivin for 24 h, the cell boundary was clear and the structure of the cells was intact. While the treating time of thiazovivin(4 µmol/L)on HCECs extended to 48 h, the immunofluorescence staining of Na(+)/K(+)-ATPase and N-cadherin showed that compared to HCECs treated with thiazovivin(4 µmol/L)for 24 h, the fluorescence intensity did not change significantly, but the cells arranged slightly untidy. In addition, the immunofluorescence staining of ROCK was weakened and the expression of ROCK was reduced by thiazovivin. Thiazovivin was effective for protecting the morphology and function of HCECs. An optimal improvement in the morphology, connection and function of HCECs was found when the primary HCECs were cultured with 4 µmol/L thiazovivin for 24 h. Moreover, the expression of ROCK protein could be significantly inhibited by thiazovivin. (Chin J Ophthalmol, 2016, 52: 686-692).

An effective indirect fluorescent antibody test for diagnosis of intestinal acariasis.

Adult mites' bodies of Dermatophagoides farinae were used as antigen in an indirect fluorescent antibody test (IFAT) to detect mite-specific IgG in sera of 48 patients with intestinal acariasis based on stool examination. Antibody titers with positive reaction ranged from 1:4 to 1:512 in 48 patients with intestinal acariasis. If antibody titers > or = 1:16 is regarded as being positive, the positive rate of patients detected with IFAT was 92%.

[Three dimensional quantitative structure activity relationship of P450(17) alpha inhibitors of 17-substituted steroids].

AIM: To develop a three dimensional quantitative structure activity relationship (3D-QSAR) model and gain further insights into the requirements for potential P450(17) alpha inhibitors. METHODS AND RESULTS: A predictive 3D pharmacophore model was established based on comparative molecular field analysis (CoMFA). The correlation between the activities and structures was significant with cross-validated value (R2cv), non-cross-validated value (R2) and standard error of estimate (SEE) of 0.538, 0.799 and 0.257, respectively. According to this model, the predicted inhibition activities of three compounds synthesized in our laboratory were compatible to actual activities. CONCLUSION: This model would contribute to the understanding of the interaction between the inhibitors and P450(17) alpha and rational design of novel lead molecules.

Antiandrogenic effects of novel androgen synthesis inhibitors on hormone-dependent prostate cancer.

We have found that in addition to being potent inhibitors of 17alpha-hydroxylase/C17,20-lyase and/or 5alpha-reductase, some of our novel androgen synthesis inhibitors also interact with the mutated androgen receptor (AR) expressed in LNCaP prostate cancer cells and the wild-type AR expressed in hormone-dependent prostatic carcinomas. The effects of these compounds on the proliferation of hormone-dependent human prostatic cancer cells were determined in vitro and in vivo. L-2 and L-10 are delta4-3-one-pregnane derivatives. L-35 and L-37 are delta5-3beta-ol-androstane derivatives, and L-36 and L-39 are delta4-3-one-androstane-derived compounds. L-2, L-10, and L-36 (L-36 at low concentrations) stimulated the growth of LNCaP cells, indicating that they were interacting agonistically with the mutated AR expressed in LNCaP cells. L-35, L-37, and L-39 acted as LNCaP AR antagonists. To determine whether the growth modulatory effects of our novel compounds were specific for the mutated LNCaP AR, competitive binding studies were performed with LNCaP cells and PC-3 cells stably transfected with the wild-type AR (designated PC-3AR). Regardless of AR receptor type, all of our novel compounds were effective at preventing binding of the synthetic androgen methyl-trienolone[17alpha-methyl-(3H)-R1881 to both the LNCaP AR and the wildtype AR. L-36, L-37, and L-39 (5.0 microM) prevented binding by >90%, whereas L-35 inhibited binding by 30%. To determine whether the compounds were acting as agonists or antagonists, LNCaP cells and PC-3AR cells were transfected with the pMAMneoLUC reporter gene. When luciferase activity was induced by dihydrotestosterone, all of the compounds were found to be potent inhibitors of transcriptional activity, and the pattern of inhibition was similar for both receptor types. However, L-2, L-10, and L-36 were determined to be AR agonists, and L-35, L-37, and L-39 were wild-type AR antagonists. When tested in vivo, L-39 was the only AR antagonist that proved to be effective at inhibiting the growth of LNCaP prostate tumor growth. L-39 slowed tumor growth rate in LNCaP tumors grown in male SCID mice to the same level as orchidectomy, significantly reduced tumor weights (P < 0.05), significantly lowered serum levels of prostate-specific antigen (P < 0.02), and significanty lowered serum levels of testosterone (P < 0.05). L-39 also proved to be effective when tested against the PC-82 prostate cancer xenograft that expresses wild-type AR. These results show that some of our compounds initially developed to be inhibitors of androgen synthesis also interact with the human AR and modulate the proliferation of hormone-dependent prostatic cancer cells. Therefore, compounds such as L-39, which have multifunctional activities, hold promise for the treatment of androgen-dependent prostate tumors.

Anti-tumour effects and pharmacokinetic profile of 17-(5'-isoxazolyl)androsta-4,16-dien-3-one (L-39) in mice: an inhibitor of androgen synthesis.

17-(5'-Isoxazolyl)androsta-4,16-dien-3-one (L-39), a novel androstene derivative, was synthesized and evaluated in vitro and in vivo. L-39 showed potent and non-competitive inhibition of human testicular microsomal 17alpha-hydroxylase/C(17,20)-lyase with an IC50 value of 59 nM and Ki of 22 nM. L-39 also showed potent and competitive inhibition of 5alpha-reductase in human prostatic microsomes with IC50 and Ki values of 33 and 28 nM respectively. L-39 (5 microM) has also been shown to manifest anti-androgenic activity in cultures of human prostate cancer cell lines (LNCaP) by preventing the labelled synthetic androgen R1881 (5 nM) from binding to the androgen receptors. Androgen-dependent human prostate cancer xenografts (PC-82) were grown in nude mice and the effects of L-39 (50 mg kg(-1) day(-1)) on tumour growth and prostate-specific antigen (PSA) levels were determined after 28 days. L-39 significantly (P < 0.01) diminished tumour growth and wet weights to a similar extent as castration or flutamide treatment. L-39 also significantly (P < 0.01) reduced serum PSA levels by more than 80% in the mice bearing human prostate cancer xenografts. Pharmacokinetic studies were also conducted in male Balb/c mice. After subcutaneous administration of a single bolus dose, L-39 was rapidly absorbed into the systemic circulation. Peak plasma levels occurred at 0.75 h and then declined with a t(1/2) of 1.51 h. The bioavailability of L-39 after subcutaneous administration was 28.5%. These results demonstrate that L-39 is a potent inhibitor of androgen synthesis and is effective in reducing the growth of human prostate cancer xenografts in nude mice. Although improvements in the bioavailability are necessary, L-39 is a potential lead compound with this profile as an inhibitor of prostate cancer growth.

Inhibition of androgen synthesis in human testicular and prostatic microsomes and in male rats by novel steroidal compounds.

The C(17,20)-lyase and 5alpha-reductase are key enzymes in the biosynthesis of androgens. The effects of novel steroidal compounds were evaluated as inhibitors against both human C(17,20)-lyase and 5alpha-reductase in vitro. The concentrations of testosterone (T) and dihydrotestosterone (DHT) in the prostate, testis and serum and changes in the tissue weights were also determined in rats treated with the novel inhibitors. L-12 and L-26 showed potent inhibition of human testicular C(17,20)-lyase with IC50 values of 50 and 25 nM, respectively. L-12, L-38, and I-47 showed moderate inhibition of human testicular C(17,20)-lyase with IC50 values of 75, 108, and 70 nM, respectively similar to ketoconazole (78 nM). Interestingly, L-6, L-26, and L-38 also showed some inhibitory activity against 5alpha-reductase with IC50 values of 75, 125, and 377 nM, respectively. Finasteride, an inhibitor of 5alpha-reductase had an IC50 value of 33 nM. However, ketoconazole did not inhibit 5alpha-reductase nor did finasteride inhibit C(17,20)-lyase. Treatment of normal male rats with several of these novel inhibitors (50 mg/kg x day, s.c., for 14 consecutive days) caused about 45-91% decrease in serum, testicular and prostatic T concentration. Similarly, serum and prostatic DHT concentration were significantly decreased in rats treated with these novel compounds by 50-90% compared with controls. Surgical castration caused almost complete elimination of circulating T and DHT concentration in rat tissues. L-6 and L-12 were the most effective and reduced the wet weight of the prostate by 50%. Although future improvements in their bioavailability are necessary, these novel steroidal compounds show promise as potential agents for reducing T and DHT levels in patients with androgen dependent diseases.

Cytochrome P450c17-expressing Escherichia coli as a first-step screening system for 17alpha-hydroxylase-C17,20-lyase inhibitors.

We have designed and synthesized a number of cytochrome P450 17alpha-hydroxylase-C17,20-lyase (P450c17) inhibitors with the aim of inhibiting androgen synthesis. To select the most potent inhibitors, we initially used human testicular microsomes, which have a high level of expression of this enzyme. However, due to lack of availability of human tissue and variability among the samples, we utilized recombinant human enzyme expressed in Escherichia coli. We designed a simple and economical protocol based on the report that recombinant bovine P450c17 can be functionally active in live bacteria. In the assay we report here, we substituted high-performance liquid chromatography product isolation with a rapid biochemical acetic acid releasing assay and utilized intact P450c17-expressing E. coli for the source of the enzyme. Enzymatic parameters of the bacterial system (Km = 5.1 x 10(-7) M, Vmax = 15.0 pmol/min/mg) were similar to those of human testicular microsomes (Km = 4.8 x 10(-7) M, Vmax = 40.0 pmol/min/mg), and our compounds displayed a similar pattern of inhibition in both systems. This new system is a fast, reliable, and reproducible method for screening P450c17 inhibitors. Furthermore, it eliminates our dependence on human tissue and potential data fluctuations caused by variations in enzymatic activity between donors.

Synthesis and in vitro activity of some epimeric 20 alpha-hydroxy, 20-oxime and aziridine pregnene derivatives as inhibitors of human 17 alpha-hydroxylase/C17,20-lyase and 5 alpha-reductase.

Some epimeric 20-hydroxy, 20-oxime, 16 alpha, 17 alpha-, 17,20- and 20,21-aziridine derivatives of progesterone were synthesized and evaluated as inhibitors of human 17 alpha-hydroxylase/C17,20-lyase (P450(17) alpha) and 5 alpha-reductase (5 alpha-R). The reduction of 16-dehydropregenolone acetate (3a) was reinvestigated. NaBH4 in the presence of CeCl3 gave better stereo-selectivity for 20 beta-ol [20 alpha/20 beta-OH (4 alpha/4 beta) = 1/2.7] than LTBAH or the Meerwein-Pondroff method reported; reduction with Zn in HOAc formed exclusively 20 alpha-ol (4 alpha b). The 20 alpha- and 20 beta-hydroxy-4,16-pregnadien-3-one (9 alpha) and (9 beta) were synthesized from the alcohols 4 alpha b and 4 beta b. Several 20-oxime pregnadienes and 16 alpha, 17 alpha-, 17,20- and 20,21-aziridinyl-5-pregnene derivatives were also synthesized. LiAlH4 reduction of the 16-en-20-oxime (12b) yielded 20 (R)-(13a) and 20(S)-17 alpha,20-aziridine (13b) and 20(R)-17 beta,20-aziridine (14a). Several compounds inhibited the human P450(17) alpha with greater potency than ketoconzole. The 5 alpha-R enzyme assay showed that while (9 alpha) did not have any activity, (9 beta) and (3b) were potent 5 alpha-reductase (IC50 = 21 and 31 nM) inhibitors with activities similar to finasteride. The 20-oximes (17a) and (17b) were potent dual inhibitors for both 5 alpha-R (IC50 = 63 and 115 nM, compared to 33 nM for finasteride) and P450(17) alpha (IC50 = 43 and 25 nM, compared to 78 nM for ketoconazole).

Effects of some novel inhibitors of C17,20-lyase and 5alpha-reductase in vitro and in vivo and their potential role in the treatment of prostate cancer.

The effects of some novel steroidal compounds were evaluated against both human C17,20-lyase and 5alpha-reductase in vitro and also against androgen synthesis in normal male rats. L-2, L-36, L-37, and I-41 showed potent inhibition of human testicular C17,20-lyase, with IC50s of 43, 39, 42, and 58 nM, respectively. In contrast, ketoconazole, a competitive inhibitor of C17,20-lyase, had an IC50 of 76 n.M. L-36 also showed potent inhibitory activity against 5a-reductase in human prostatic microsomes, with an IC50 of approximately 31 nM. The inhibitory activities of L-2 and 1-41 on 5alpha-reductase were moderate, with IC50s of 75 and 151 nM, respectively, whereas L-37 showed little inhibitory activity against this enzyme. In comparison, finasteride, a potent inhibitor of 5alpha-reductase, had an IC50 of 33 nM. When normal male rats were treated with these novel compounds (50 or 100 mg/kg/day) for 14 consecutive days, the wet weight of the prostate was significantly reduced by L-36, L-37, and I-41, compared to the control group. Testosterone levels in rat serum were also reduced by L-36 (55%), L-37 (86%), and I-41 (53%). The concentrations of testosterone in rat testes were reduced by these novel compounds by 13-74%. The compounds also reduced the concentration of testosterone in rat prostates by 35-75%. Similarly, dihydrotestosterone (DHT) concentration in rat serum was reduced 30-89% by these compounds, compared to the control group. Prostatic DHT levels were also lower in rats treated with L-36 (48%), L-37 (54%), or I-41 (26%). In contrast, L-2 enhanced serum testosterone and prostatic DHT concentrations by >50%. These findings suggest that the dual activities of several of these novel inhibitors of C17,20-lyase and 5alpha-reductase accounts for the diminished levels of circulating androgens in vivo.

17-Imidazolyl, pyrazolyl, and isoxazolyl androstene derivatives. Novel steroidal inhibitors of human cytochrome C17,20-lyase (P450(17 alpha).

We recently described a number of inhibitors of P450(17 alpha), the key enzyme of androgen biosynthesis. Here, we report the synthesis and activity of novel 17-imidazolyl, pyrazolyl, and isoxazolyl androstene derivatives as potential agents for the treatment of prostatic cancer. A number of 17-(4'-Imidazolyl) derivatives were prepared by condensing the corresponding 17-ketol acetate side chain with aldehyde and ammonium hydroxide. The 17 beta-(4'imidazolyl) derivatives (2a, 2e, 4a, 4c) were found to be potent inhibitors of human testicular P450(17 alpha), with greater activity than ketoconazole. The juxtaposition between the imidazole ring and the steroid D ring appears to be important in contributing inhibitory properties, Compounds having a 17 beta-(2'-imidazolyl) ring (9a, 10) or a 20 beta-(2'-imidazolyl) ring (12), instead of the 17 beta-(4'-imidazolyl) ring (2a, 4a), are weak inhibitors. Among the 17-(4'-imidazolyl) derivatives, introduction of the 17 alpha-hydroxy group (4b) and 16 alpha,17 alpha-epoxide group (2d) diminished potency (2a-->2d; lC50 66-->430 nM; 4a-->4b; lC50 58-->1200 nM), while the 16,17 double bond increased the inhibitory activity by almost three times in the 5-en-3 beta-ol inhibitors (2a-->2e; lC50 60-->24 nM). There was virtually no difference in the inhibitory activity in the 4-en-3-one inhibitors (4a-->4c; IC50 58-->50 nM). The introduction of a methyl (2b) or phenyl group (2c) on the 2'-position of 4'-imidazolyl ring caused a dramatic decrease in the potency. As to modification of the A,B rings, the 3-acetate (2f, 2g) decreased the potency almost 3-fold compared with the 3-alcohol (2e-->2f, IC50 24-->75 nM; 2a-->2g, 66-->199 nM) and the conversion from the 5-en-3 beta-ol into the 4-en-3-one hardly affected the potency. As expected, 4c was more potent than 2e for the rat p450(17 alpha). 17-(3'Pyrazolyl)-(14b) and 17-(5'-isoxazolyl)-androsta-5,16-dien-3 beta-ol (15b) were also potent inhibitors of P450(17 alpha), whereas the 17-(2'-imidazolyl) compound (9b) was one of the most potent inhibitor in this series. However, their 16-saturated counterparts (9a, 14a, 15a) were weak inhibitors. The 17 beta-(3'-isoxazolyl)- (16) and 17 beta-(5'-methyl-3'-oxazolyl)androst-5-en-3 beta-ol (18) were also inactive. The introduction of a methyl of phenyl group on the nitrogen of the pyrazolyl ring of 14b [see 14c, 14d, and 14e] also caused some loss of inhibition for P450(17 alpha). Compounds 2e, 4a, 4c, 9b, 14d, 17a, and 17b are among the most potent inhibitors of human P450(17 alpha) so far reported.

Growth inhibition of human prostate cells in vitro by novel inhibitors of androgen synthesis.

The long-standing strategy for the treatment of metastatic prostate cancer has been to reduce androgenic stimulation of tumor growth by removal of the testes, the primary site of testosterone synthesis. However, a low level of androgenic stimulation may continue, even after castration, by the conversion of adrenal androgens to 5alpha-dihydrotestosterone (DHT) in the prostate tumor cells. Two important enzymes of the androgen biosynthetic pathway are 17alpha-hydroxylase/C17,20-lyase, which regulates an early step in the synthesis of testosterone and other androgens in both the testes and adrenal glands, and 5alpha-reductase, which converts testosterone to the more potent androgen, DHT, in the prostate. We have identified new inhibitors of these enzymes that may be of use in achieving a more complete ablation of androgens in the treatment of metastatic prostate cancer. Three derivatives of androstene were shown to inhibit 17alpha-hydroxylase/C17,20-lyase with potencies 2-20-fold greater than that of ketoconazole, a previously established inhibitor of this enzyme. Derivatives of pregnane and pregnene displayed activities against 5alpha-reductase that were comparable to that of N-(1,1-dimethyl-ethyl)-3-oxo-4-aza-5alpha-androst-1-ene-17beta-car boxamide. All of the 5alpha-reductase inhibitors were able to at least partially inhibit the mitogenic effect of testosterone in either histocultures of human benign prostatic hypertrophic tissue or in cultures of the LNCaP human prostatic tumor cell line. For these compounds, it appears that this inhibition can be attributed to a reduction of DHT synthesis in these cultures, because no inhibitory effect was observed in DHT-treated cultures, and none of the compounds had a cytotoxic effect. Surprisingly, one of the inhibitors of 17alpha-hydroxylase/C17,20-lyase, 17beta-(4-imidazolyl)-5-pregnen-3beta-ol, was also able to inhibit the mitogenic effect of testosterone in both the histoculture and cell culture assays and had an effect against DHT as well. In transcriptional activation assays, it was found that this compound is an antagonist of both the wild-type androgen receptor and the mutant androgen receptor, which is present in LNCaP cells. In conclusion, the abilities of these compounds to inhibit androgen synthesis and, in some cases, to exert antiandrogen activity, did in fact translate to an inhibitory effect on the growth of human prostatic tissue in vitro, suggesting their potential utility in the treatment of prostatic cancer.

[Studies on semi-synthesis of cephalotaxine esters and correlation of their structures with antitumor activity].

Ten esters of cephalotaxine with amino acids possessing widely different structural features have been synthesized and tested for antitumor activity. Preliminary data showed that compound 6 is the most active one. However, it is still less potent than harringtonine. Other synthetic esters possess varying activities at 10 micrograms/ml. Preliminary structure activity relationship of these esters was discussed.

[Studies on the anticonvulsive activity of pyrazolidinones].

The anticonvulsive activity of three kinds of pyrazolidinones: 5-benzyl-substituted-3-pyrazolidinones; 5-benzyl-1-alkyl substituted and 1-alkyl substituted-3-pyrazolidinones were studied. Fourteen substitutes of these three kinds of pyrazolidinones were found to be potent anticonvulsants. In doses less than TD50, they were found to be able to protect mice and rats from seizures produced by maximal electroshock seizure (MES), such action appeared rapidly and lasted for a short period. II-f was shown to be the most potent anti-MES agent among these three kinds of pyrazolidinones. It also showed therapeutic effect in treating experimental epilepsy produced by intrahippocampal injection of zinc sulfate in rabbits and audiogenic seizures in rats. The third kind of pyrazolidinones also showed anti-metrazol induced seizures in mice.

[Study of the relationship between structure and anticonvulsant activities of 5-substituted-1-butry-3-pyrazolidinones and their synthesis].

According to the quantitative structure-activity relationship studies of 3-pyrazolidinones with different substituent on positions 1 and 5 reported previously, the anticonvulsant activity is parabolically related with the total fragment constent (Fr hydrophobic parameter) of the 1 and 5 substituents of 3-pyrazolidion. The optimum Fr was about 5.6. Therefore, eleven new 5-substituted-3-pyrazolidinones have been synthesized. Pharmacological test showed that they are all potent anticonvulsant agents. Among them 1-n-butyl-5-(p-chlorophenyl)-3-pyrazolidinone was shown to be the most potent so far synthesized.

[QSAR studies on the anticonvulsant activity of 5-substitutedphenyl-1-hydro- and 1-propyl-3-pyrazolidinones].

The chemical structure and anticonvulsant activity relationship of some 5-substituted phenyl-3-pyrazolidinone derivatives were studied. Six pairs (1-hydro and 1-propyl substituted) of compounds were designed and synthesized according to the Topliss improved method, and a compound with the highest anticonvulsant activity was found, i.e. 5-(4-fluorophenyl)-1-propyl-3-pyrazolidinone, ED50 14.7 mg/kg (MES Test). QSAR analysis showed that the hydrophobic constant sigma pi greatly influenced their anticonvulsant activity, and the steric parameter (B4) and electronic parameter (I x 10(2] of the substitutions on the phenyl ring can improve the correlation coefficient (r). Smaller steric volume and more powerful electron withdrawing effect of the substitution on the 5-phenyl ring increased the anticonvulsant activity.