Synthesis and antiandrogenic activity of some new 3-substituted androstano[17,16-c]-5'-aryl-pyrazoline and their derivatives

A series of androstano[17,16-c]pyrazolines and their oxidized derivatives (2-14) were synthesized using 3beta-hydroxyandrostan-17-one as a starting material (1a, b). The synthesized compounds were evaluated for their antiandrogenic activity compared to that of Cyproterone as positive control. Some of the compounds exhibited better antiandrogenic activity than the reference drug. The detailed synthesis, spectroscopic data, ED(50), and toxicity (LD(50) and LD(90)) of the synthesized compounds were reported.     

Synthesis of aldehydo-sugar derivatives of pyrazoloquinoline as inhibitors of herpes simplex virus type 1 replication

Synthesis of a novel series of structurally related pyrazoloquinoline nucleosides is described. All the newly synthesized compounds were examined for their in vitro antiviral activity against herpes simplex type-1 as shown by two different bioassays, namely; crystal violet staining or the MTS tetrazolium dye measurement. The acute toxicity (LD50) values of the biologically active compounds were determined.     

Synthesis of Aldehydo-sugar Derivatives of Pyrazoloquinoline as Inhibitors of Herpes Simplex Virus Type 1 Replication

Synthesis of a novel series of structurally related pyrazoloquinoline nucleosides is described. All the newly synthesized compounds were examined for their in vitro antiviral activity against herpes simplex type-1 as shown by two different bioassays, namely; crystal violet staining or the MTS tetrazolium dye measurement. The acute toxicity (LD50) values of the biologically active compounds were determined.     

General characteristics and comparative evaluation of the radioprotective properties of aryl alkyl amine adrenomimetics in experiments on mice]

The radioprotective effect (RPE) of some arylalkylamines (AAAs) was studied in experiments on mice. Mesaton and its close analogues were injected subcutaneously 15 minutes prior to irradiation at a dose of 800 rad. The protective effect is exerted by AAAs in low doses (25--50 mumole/kg), the compounds show stable and high RPE (80--80% survival, dose reduction factor being 1.3--1.4) and low toxicity (LD50 = 4--8 mumole/kg). AAAs studied are not less effective than aminothiols. Their pharmacological spectrum--K = LD50/ED50 (200--500) is superior to that of known aminothiols and indolylalkylamines.     

Comparative analysis of in vitro antifungal activity and in vivo acute toxicity of the nystatin analogue S44HP produced via genetic engineering]

New polyene macrolide S44HP was purified from the culture of recombinant Streptomyces noursei strain with engineered nystatin polyketide synthase. S44HP, nystatin (NYS), and amphotericin B (Amph-B) were tested against 19 clinical fungal isolates in agar diffusion assay, which demonstrated clear differences in antifungal activities of these antibiotics. Sodium deoxycholate suspensions of all three antibiotics were subjected to acute toxicity studies in vivo upon intravenous administration in mice. NYS exhibited the lowest acute toxicity in mice in these experiments, while both Amph-B and S44HP were shown to be 4 times more toxic as judged from the LD50 values. While the acute toxicity of S44HP was higher than that of Amph-B, the data analysis revealed a significantly increased LD10 to LD50 dose interval for S44HP compared to Amph-B. The data revealed structural features of polyene macrolides, which might have an impact on both the activity and toxicity profiles of these antibiotics. These results represent the first example of preclinical evaluation of an "engineered" polyene macrolide, and can be valuable for rational design of novel antifungal drugs with improved pharmacological properties.     

Steroidal pyrazolines evaluated as aromatase and quinone reductase-2 inhibitors for chemoprevention of cancer

The aromatase and quinone reductase-2 inhibition of synthesized heterocyclic pyrazole derivatives fused with steroidal structure for chemoprevention of cancer is reported herein. All compounds were interestingly less toxic than the reference drug (Cyproterone(?)). The aromatase inhibitory activities of these compounds were much more potent than the lead compound resveratrol, which has an IC(50) of 80 μM. In addition, all the compounds displayed potent quinone reductase-2 inhibition. Initially the acute toxicity of the compounds was assayed via the determination of their LD(50). The aromatase and quinone reductase-2 inhibitors resulting from this study have potential value in the treatment and prevention of cancer.     

Anti-inflammatory profile of some synthesized heterocyclic pyridone and pyridine derivatives fused with steroidal structure

We herein report the anti-inflammatory activity of some newly synthesized heterocyclic pyridone and pyridine derivatives fused with steroidal structure. Initially the acute toxicity of the compounds was assayed via the determination of their LD(50). All compounds, except 3b, 22, and 23, were interestingly less toxic than the reference drug (Prednisolone). Regarding the protection against Carrageenan-induced edema, eight compounds were found to be more potent than Prednisolone. On the other hand, in searching for COX-2 inhibitor, the inhibition of plasma PGE2 for the compounds was determined and four compounds were found to be more potent than the reference drug. The structure assignment of the new compounds was based on chemical and spectroscopic evidence.     

Design, synthesis and biological evaluation of some pyrazole derivatives as anti-inflammatory-antimicrobial agents

The synthesis of novel series of structurally related 1H-pyrazolyl derivatives is described. All the newly synthesized compounds were tested for their in vivo anti-inflammatory activity by two different bioassays namely; cotton pellet-induced granuloma and sponge implantation model of inflammation in rats. In addition, COX-1 and COX-2 inhibitory activities, ulcerogenic effects and acute toxicity were determined. The same compounds were evaluated for their in vitro antimicrobial activity against Escherichia coli, as an example of Gram negative bacteria, Staphylococcus aureus as an example of Gram positive bacteria, and Candida albicans as a representative of fungi. The combined anti-inflammatory data from local and systemic in vivo animal models showed that compounds 4, 5, 8, 9, 11 and 12a exhibited anti-inflammatory activity comparable to that of indomethacin with no or minimal ulcerogenic effects and high safety margin (LD(50)>500 mg/Kg). In addition, compounds 4, 7, 10, 12a and 12b displayed appreciable antibacterial activities when compared with ampicillin, especially against S. aureus. Compounds 4 and 12a are the most distinctive derivatives identified in the present study because of their remarkable in vivo and in vitro anti-inflammatory potency and their pronounced antibacterial activities comparable to ampicillin against Gram positive. On the other hand, compound 12a exhibited good selective inhibitory activity against COX-2 enzyme. Therefore, such compound would represent a fruitful matrix for the development of anti-inflammatory-antimicrobial candidates.     

QRAR models for cardiovascular system drugs using biopartitioning micellar chromatography

The capability of biopartitioning micellar chromatography (BMC) to describe and estimate pharmacological parameters of cardiovascular system drugs has been studied. The retention of cardiovascular system drugs was studied using different pH of Brij-35 as micellar mobile phase in modified C(18) stationary phase. Quantitative retention-activity relationships (QRAR) in BMC were investigated for these compounds. An adequate correlation between the retention factors (log k) and the toxicity (LD(50)) of cardiovascular system drugs was obtained.     

5α-reductase inhibitors, antiviral and anti-tumor activities of some steroidal cyanopyridinone derivatives

We herein report the 5α-reductase inhibitors, antiviral and anti-tumor activities of some synthesized heterocyclic cyanopyridone and cyanothiopyridone derivatives fused with steroidal structure. Initially the acute toxicity of the compounds was assayed via the determination of their LD₅₀. All the compounds, except 3b, were interestingly less toxic than the reference drug (Prednisolone^®). Seventeen heterocyclic derivatives containing a cyanopyridone or cyanothiopyridone rings fused to a steroidal moiety were synthesized and screened for their 5α-reductase inhibitors, antiviral and anti-tumor activities comparable to that of Anastrozole, Bicalutamide, Efavirenz, Capravirine, Ribavirin, Oseltamivir and Amantadine as the reference drugs. Some of the compounds exhibited better 5α-reductase inhibitors, antiviral and anti-tumor activities than the reference drugs. The detailed 5α-reductase inhibitors, antiviral and anti-tumor activities of the synthesized compounds were reported.     

Antihistamine, anticholinergic and cardiovascular effects of 2-substituted-4-phenylquinoline derivatives

Eleven new derivatives of 4-phenylquinoline, having various substituents at the 2-position of the quinoline ring, were previously synthesized. The antidepressant activities of these derivatives were demonstrated by their antagonism to reserpine-induced hypothermia in mice. The ED50 values were found to be in the range of 12-42 mg/kg (imipramine is 21.0 mg/kg). In the present work, comparative studies of the effects of these new drugs on the cholinergic and histaminergic (H1) systems, as well as their effects on the cardiovascular system, are presented. Both imipramine and trazodone were utilized as standards representing typical and atypical antidepressant drugs, respectively. All these new compounds have very low antihistaminic (H1) activities, as compared to imipramine. In addition, a clear cut separation of the antidepressant activity from the antihistaminic (H1) activity was observed. These compounds have weak anticholinergic (atropine-like properties) activity as compared to imipramine, using the isolated guinea-pig ileum. Animal studies of the cardiac toxicity of these compounds showed reduced lethality for some of them as compared to imipramine. Arrhythmias commonly associated with imipramine were absent for most of these compounds. The effects of these compounds on the heart conduction were determined by electrocardiographic studies. Although some of these compounds do not interfere with heart conduction, as compared to imipramine most were inferior to trazodone. Correlation between the pharmacological activities and structural modifications of these derivatives has also been observed.     

Design and synthesis of 1,3-benzothiazinone derivatives as potential anti-inflammatory agents

A series of 1,3-benzothiazinone derivatives were designed and synthesized for pharmacological assessments. Among the synthesized 19 compounds, some compounds showed high activities on inhibiting LPS-induced nitrite oxide and TNF-α production, down-regulating COX-2 and increasing IL-10 production in RAW264.7 cells. All the compounds had no obvious cytotoxicity in in vitro assay. LD₅₀ value of compound 25 was greater than 2000 mg/kg, which was safer than meloxicam. Compound 25 significantly inhibited phosphorylation of NF-κB and STAT3 in LPS-induced RAW264.7 cells. Inhibition of synthesized compounds on COX activity was weaker than meloxicam. Compound 25 displayed lower gastrointestinal toxicity than meloxicam. Besides, compound 25 decreased the swelling in carrageenan-induced paw edema models of inflammation and reduced PGE₂ level significantly. In summary, 1,3-benzothiazinone derivatives are unique scaffolds with anti-inflammatory activity and low toxicity.     

Anti-barnacle activity of novel simple alkyl isocyanides derived from citronellol

Twenty novel simple alkyl isocyanides derived from citronellol were synthesized and evaluated for their antifouling activity and toxicity against cypris larvae of the barnacle, Balanus amphitrite. The anti-barnacle activity of the synthesized isocyanides was in the EC(50) range of 0.08-1.49 μg ml(-1). Simple isocyanides containing a benzoate and chloro group showed the most potent anti-barnacle activity. In addition, none of the synthesized compounds showed significant toxicity and LC(50) values were <10 μg ml(-1). The LC(50)/EC(50) ratios of almost all of the synthesized compounds were >10(2). The results indicate that these simple isocyanides are promising low-toxicity antifouling agents.     

Design, synthesis, and biological evaluation of chalcone oxime derivatives as potential immunosuppressive agents

A series of deoxybenzoin oximes were recently reported as potent immunosuppressive agents by our group. In order to continue the original research for potential immunosuppressive agents with high efficacy and low toxicity, we synthesized a series of new chalcone oximes and evaluated them for their cytotoxicities and immunosuppressive activities. Among the synthesized compounds, chalcone oximes 25 and 27 exhibited lower cytotoxicities and higher inhibitory activities on anti-CD3/anti-CD28 co-stimulated lymph node cells than other compounds. Specially, compound 27 displayed 200-fold lower cytotoxicity (CC(50)=2174.39 μM) than cyclosporin A (CC(50)=10.10 μM) and showed SI value (SI=176.69) close to cyclosporin A (SI=154.13). Besides, the preliminary mechanism of inhibition effect of compounds 25 and 27 was also detected by flow cytometry, and the compounds exerted immunosuppressive activities via inducing the apoptosis of activated lymph node cells in a dose dependent manner. Also, the deep mechanism of apoptosis was detected by Western blot analysis.     

狼毒活性部位复合乳油功效

为增强瑞香狼毒制剂的杀虫药效、充分开发利用以瑞香狼毒为主的植物源农药,进行了瑞香狼毒杀虫活性部位与其它药物的复配实验。采用瑞香狼毒杀虫活性部位(LD)分别与烟碱乳油(YJR)、CT-901A(Bz)的不同质量比,在室内对家蝇、酢酱草茹叶螨(Petrbia hartiEwing)进行毒力测定,利用软件进行毒力回归分析。实验结果显示,LD和YJR、LD和Bz的两两复配及三者(LD YJR Bz)的复配能够起显著增效作用,特别是20:1:1(LD:YJR:Bz)、30:1:1(LD:YJR:Bz)对家蝇的毒力效果更加明显,LC50达到了0.005 mg/L,20:1(LD:Bz)、30:1(LD:Bz)、30:1:1(LD:YJR:Bz)对酢酱草茹叶螨(Petrbia hartiEwing)的毒力效果也同样显著,LC50也达到了0.005 mg/L。并对瑞香狼毒活性部位进行初步分离检测,其有效成分为黄酮类物质。     

Genotoxic activity of newly synthesized derivatives of cyano-pyridone in murine cells in vivo and in vitro

Possible genotoxic activity of two newly synthesized cyanopyridone compounds [4-(N-methyl-phalimidyl-3)-3-cyano-4-methyl-pyridone-2 (MPhCMP) and 1-(4-hydroxyphenyl)-3-cyano-4-methyl-pyridone-2 (HCMP)] with in vitro antitumor activity was studied both in in vitro and in vivo murine test systems. In L5178Y mouse lymphoma cells, HCMP did not induce micronuclei (MN) at the highest available (because of toxicity) concentration (100 microg/ml), while MPhCMP at dose of 50 microg/ml induced 2.6-fold, and at dose of 100 microg/ml 3.95-fold increase of number of the cells with MN. The concentration of 100 microg/ml is a threshold of toxicity of MPhCMP. In experiments on possible DNA damaging activity (the comet assay) of both substances using the same doses as in in vitro mutagenesis assay, we did not reveal any evidence of DNA damage. The acute toxicity of compounds was studied on male Swiss albino mice. LD50 values of MPhCMP and HCMP were 177.5 and 288 mg/kg, respectively. MPhCMP was more potent MN inductor than HCMP (2.5-fold at doses equivalent to 1/2 of LD50). Both substances possessing in vitro antitumor activity along with weak genotoxicity have a good chance for successful in vivo antitumor studies in rodents.     

Antinociceptive and acute toxicity evaluation of Vernonia condensata Baker leaves extracted with different solvents and their mixtures

Extract of Vernonia condensata (Asteraceae = Compositae) leaves has different uses in Brazilian folk medicine, which includes analgesic and antiinflamatory agent. The aim of this study was to apply a modified simplex-centroid mixture design to evaluate the best extractor system for the antinociceptive activity, evaluated by writhing test. Different solvents (acetone, dichloromethane, ethanol and ethyl acetate) as well as their binary, ternary and quaternary mixtures were used. For comparison, aqueous extract was also evaluated. LD50 was estimated and qualitative phytochemical screening, conducted. The extracts with antinociceptive activity were: aqueous, acetone, dicloromethane (DCM), ethanol (ETOH), acetone-DCM, acetone-ETOH, acetone-ethyl acetate, ETOH-ethyl acetate, acetone-DCM-ethyl acetate, acetone-ETOH-ethyl acetate and DCM-ETOH-ethyl acetate. The higher margin of safety (LD50/ED50) was for acetone > acetone-ETOH-ethyl acetate > aqueous > ETOH = acetone-ETOH > DCM > acetone-ethyl acetate > DCM-ETOH-ethyl acetate > acetone-DCM > acetone-DCM-ethyl acetate. Phytochemical screening showed that all the extracts contained alkaloids, phenolic compounds, flavonoids, tannins and saponins. In conclusion, the extractor system influences both the pharmacological activity and acute toxicity of leaves from V. condensata. Acetone and the ternary mixture, acetone-ETOH-ethyl acetate extracts showed higher margin of safety than aqueous extract.     

土荆芥生物总碱对家蝇的毒杀作用及药剂敏感性的影响

通过室内毒力测定和生化分析方法,测定了土荆芥生物总碱对敌百虫抗性种群,溴氰菊酯抗性种群,敏感种群等3个家蝇(Musca domestica)种群成虫的毒杀效果,土荆芥生物总碱处理前后家蝇种群成虫对溴氰菊酯和敌百虫的药剂敏感性变化,以及对家蝇成虫羧酸酯酶和谷胱甘肽-S-转移酶的活力的影响。结果表明,土荆芥生物总碱不仅对家蝇有毒杀效果,处理后能提高家蝇对杀虫剂的敏感性,而且能抑制家蝇体内解毒酶系活性。土荆芥生物总碱对不同种群家蝇成虫的LD_(50)没有显著差异;土荆芥生物总碱处理前后,敌百虫对抗性种群和敏感种群的LD_(50)比值分别为1.6277和1.2914,溴氰菊酯对抗性种群和敏感种群的LD_(50)比值分别为2.0768和1.3871;土荆芥生物总碱处理前后,家蝇敌百虫抗性种群、溴氰菊酯抗性种群和敏感种群成虫的羧酸酯酶活性比值分别为1.1692、1.2947和1.2259,谷胱甘肽-S-转移酶活性比值分别为1.2476、1.6519和1.0570。     

Antifouling activity of simple synthetic isocyanides against larvae of the barnacle Balanus amphitrite

Twelve simple linear isocyanides were synthesized and examined for antifouling activity and toxicity against cyprid larvae of the barnacle, Balanus amphitrite. Larval settlement was inhibited, with EC50 values of 0.046-1.90 microg ml(-1), and they were much less toxic (LD50 values ranging over 21.28 microg ml(-1)) than CuSO4 (EC50 0.30 microg ml(-1) and LD50 2.95 microg ml(-1)). The data indicate that simple linear isocyanides are promising non-toxic antifouling agents.     

Trypanocidal and cytotoxic evaluation of synthesized thiosemicarbazones as potential drug leads against sleeping sickness

Thiosemicarbazones have become one of the promising compounds as new clinical candidates due to their wide spectrum of pharmaceutical activities. The wide range of their biological activities depends generally on their related aldehyde or ketone groups. Here, we report the pharmacological activities of some thiosemicarbazones synthesized in this work. Benzophenone and derivatives were used with N(4)-phenyl-3-thiosemicarbazide to synthesize corresponding five thiosemicarbazones (1–5). Their structures were characterized by spectrometrical methods analysis IR, NMR ¹H & ¹³C and MS. The compounds were then screened in vitro for their antiparasitic activity and toxicity on Trypanosoma brucei brucei and Artemia salina Leach respectively. The selectivity index of each compound was also determined. Four thiosemicarbazones such as 4, 2, 3 and 1 reveal interesting trypanocidal activities with their half inhibitory concentration (IC₅₀) equal to 2.76, 2.83, 3.86 and 8.48 μM respectively, while compound 5 (IC₅₀ = 12.16 μM) showed a moderate anti-trypanosomal activity on parasite. In toxicity test, except compound 1, which showed a half lethal concentration LC₅₀ >281 μM, the others exerted toxic effect on larvae with LC₅₀ of 5.56, 13.62, 14.55 and 42.50 μM respectively for thiosemicarbazones 4, 5, 3 and 2. In agreement to their selectivity index, which is greater than 1 (SI >1), these compounds clearly displayed significant selective pharmaceutical activities on the parasite tested. The thiosemicarbazones 2–5 that displayed significant anti-trypanosomal and cytoxicity activities are suggested to have anti-neoplastic and anti-cancer activities.