Earticle

Pyrazole, β-lactam, salicidine, pyren and oxazole derivatives exhibit a broad spectrum of biological activities such as antimicrobial, anti-inflammatory and antitumor activities. With growing application on their synthesis and bioactivity, chemists and biologists in recent years have considerable attention on the research of these derivatives. In the view of potential importance of these derivatives, we have crystallized few of the derivatives and its report has been published. The present study focuses on docking studies of these derivatives against COX-2 enzyme. Docking studies using Schrodinger’s GLIDE reveals that these derivatives shows better binding energy and score in the defined active site. These results may provide a guiding role to design a lead molecule which may reduce inflamation.

In view of the growing medicinal importance of pyrazole and its derivatives, the single crystal X-ray diffraction study was carried out for the potential active 2-Benzyl-3-[3-(4-bromo-phenyl)-1-phenyl-1H-pyrazol-4yl]-4,6- dioxo-5-phenyloctahydro- pyrrolo[3,4-C]pyrrole-1-carboxylic acid ethyl ester (C37H31BrN4O4, H2O). In the title compound are two molecules exist in the asymmetric unit. It crystallizes in the monoclinic space group Pî with unit cell dimension a=13.361 (18) Å, b=13.424 (17) Å and c=21.649 (2) Å [α=80.745 (9)o, β=79.770 (10)o and γ=60.788 (6)o]. The pyrazole ring adopts planar conformation. The sum of the bond angles at nitrogen atom of the pyrazole ring indicates the Sp2 hybridized state. The crystal structure is stabilized by intramolecular C-H...O hydrogen bond interaction.

The crystal structure of the potential active 2-amino-4-(4-hydroxy-3-methoxyphenyl)-7, 9-dimethyl-5-oxo-4, 5, 6, 7- tetrahydropyrano [2, 3-d] pyrazolo [3, 4-b] pyridine-3-carbonitrile (C21H22N5O6S) has been determined from single crystal X-ray diffraction data. In the title compound crystallizes in the monoclinic space group P-1 with unit cell dimension a=8.1201(9)Å, b=12.2684(4)Å and c= 12.387(2)Å [α=69.573o, β= 12.168o and γ=76.060o]. In the structure the pyrazole, pyridine and pyran are almost coplanar each other. The crystal packing is stabilized by intermolecular C-H...O and NH... O hydrogen bond interaction.

Pyrazole, hydroxyimino, aldehyde and isoxazole derivatives exhibit a broad spectrum of biological activities such as antimicrobial, anti-inflammatory and antitumor activities. With growing application on their synthesis and bioactivity, chemists and biologists in recent years have considerable attention on the research of these derivatives. In the view of potential importance of these derivatives, we have crystallized few of the derivatives and its report has been published. The present study focuses on docking studies of these derivatives against Phospholipases A2 enzyme. This enzymes has implicated as potential targets for anti-inflammatory drug design. co-crystal structure (PDB ID: 1POE) of PLA2 deposited in Protein Data Bank has been retrieved for docking analysis. Docking studies using Schrodinger’s GLIDE reveals that these derivatives shows better binding energy and score in the defined active site. These results may provide a guiding role to design a lead molecule which may reduce inflamation.

Thiocarboxamidocinnamonitrile derivatives 2 under bar a-f reacted with 3-aminopyrazole derivative 3 under bar a-c to give the pyrazole[3, 2-b]pyrimidine derivatives 6 under bar a-p. Compounds 6 under bar a-p were used as starting material for syntheses of several heterocylic coompounds. Dehydrogenation of 6 under bar gave pyrazole[3, 2-b]pyrimidines 10 under bar a-d while its reaction with diethyl oxalate gave 11 under bar. Reactions of 6 under bar with formic acid gave pyrazolopyrimidines 17 under bar a-j, and pyrazolopyrimidopyrimidines 18 under bar a-j.

Pyrazole 유도체들인 1,2,4-triazolidine-3,5-dione(1)과 1,3,4-oxa(or thia) diazolidine-2,5-dione(2,3)의 lactam-lactim tautomer들을 ab initio, AM1 그리고 PM3 방법으로 연구하였다. 세 가지 방법에서 모두 1 화합물의 가장 안정한 형태는 dilactam인 1a이고 다음으로 lactam-lactim인 2b로 결정되었댜. 계산방법에 따라 1a와 1b의 에너지 차이는 4.1~12.6kcal/mol로 계산되었다. 1a에 대한 ab initio 구조는 X-ray 구조와 잘 일치하고 있다. 2 화합물의 안정도는 2a>2b>2c인 반면 황원자를 포함하고 있는 3 화합물 tautomer들간의 안정도 순서는 계산방법에 의존된다. 3-21G에서는 3a가 3b보다 4.9kcal/mol 안정한 반면 AM1은 3b가 2.71kcal/mol 안정한 결과를 얻었다.

Molecular orbital calculations at the ab initio, AM1, and PM3 levels have been carried out to investigate the lactam-lactim tautomerism of 1,2,4-triazolidine-3,5- dione(1) and 1,3,4-oxa(or thia)diazolidine-2,5-dione(2, 3). Most stable tautomer in 1 compound has been calculated to be a dilactam 1a and next one is lactam-lactim 1b. The relative energies between 1a and 1b are 4.1~12.6 kcal/mol depending on computational methods. The optimized 1a structure at ab initio level is in good agreement with X-ray structure. While the stabilities of 2 tautomers are in order of 2a>2b>2c, the stabilities of 3 tautomers are dependent on methods. According to 3-21G basis set, 3a tautomer is more stable by 4.9 kcal/mol over 3b tautomer. In contrast, the heat of formation of 3a at AM1 is higher by 2.71 kcal/mol than 3b.

Pyrazole계(系) 제초제(除草劑) pyrazolate, pyrazoxyfene 및 benzophenap과 Chloroacetamide계(系) 제초제(除草劑) butachlor 및 pretilachlor의 혼합처리시(混合處理時) 피에 대한 살포작용(殺草作用)에 있어서의 상호작용(相互作用)을 천판(千坂)의 등효과선법(等效果線法)과 Colby의 상호작용검정법(相互作用檢定法)으로 검정(檢定)해 본 결과(結果)는 다음과 같다. 1. Pyrazole계(系)의 10a당(當) 300g ai 수준(水準)에서의 피의 생육억제율(生育抑制率)은 pyrazolate 경우 1.5엽기(葉期) 피해 eoo 44%, pyraxoxyfene 경우 1.5엽기(葉期) 피에 대해 64%이었고, benzophenap의 피 초엽기에 60% 억제(抑制)할 뿐 1엽기(葉期) 이상(以上)에서는 억제(抑制)하지 못하였으며, chloroacetamide계(系)의 경우 butachlor는 150g ai/10a 수준(水準)에서, 그리고 pretilachlor는 20g ai/10a 수준(水準)에서 1.5엽기(葉期) 피를 99% 정도(程度) 억제(抑制)하였다. 2. Pyrazolate와 butachlor의 혼합처리(混合處理), pyrazoxyfene과 pretilachlor의 혼합처리(混合處理)는 피 1.5엽기(葉期) 또는 초엽기에 모두 상승적(相乘的) 상호작용(相互作用)을 보였는데 상호적(相互的) 상호작용(相互作用)은 정도(程度)는 pyrazolate/butachlor(공력작용지수(共力作用指數)=2.4) > pyrazoxyfene / pretilachlor(공력작용지수(共力作用指數) = 1.62) > benzophenap / butachlor(공력작용지수(共力作用指數)=1.52) 순위(順位)이었다. 3. Pyrazole계(系)와 Chloroacetamide계(系) 제초제(除草劑) 혼합처리(混合處理)에서 피의 생육(生育) 90% 억제등효과선상(抑制等效果線上) 최고(最高)의 공역효과(共力效果)가 나타난 약량수준(藥量水準) 및 약량비율(藥量比率)은 pyrazolate/butachlor 혼합(混合)의 경우 187g/14g ai/10a (1:0.075)이었고, pyrazoxyfene/pretilachlor 조합(組合)의 경우 330g/3.3g ai / 10a(1:0.01)이었으며, benzophenap/butachlor의 경우 335g/52g/ ai/10a(1:0.15)이었다.

Three pyrazole-herbicides, pyrazolate, pyrazoxyfene and benzophenap, were evaluated for their interaction in controlling barnyardgrass (Echinochloa crusgalli) with two chloroacetamide-herbicides, butachlor and pretilachlor. Percent inhibition of barnyardgrass growth by pyrazolate, pyrazoxyfene, and benzophenap was 44%, 64%, and 0%, respectively, when each was applied at the 1.5 leaf-stage of barnyardgrass at a rate of 3㎏ ai per ㏊ as single treatment, and the benzophenap showed 60% inhibition when it was applied at the coleoptile stage. While the lowest rate controlling the 1.5 leaf-stage barnyardgrasses by 98 to 100% of the butachlor and pretilachlor was 1.5㎏ and 200g per ㏊, respectively. All of the combinations of pyrazolate with butachlor, pyrazoxyfene with pretilachlor, and benzophenap with butachlor have shown synergistic interaction in controlling barnyardgrass on the Chisaka's isobole of 90% growth inhibition as well as on the Colby`s interaction efficacy data; synergism indices were 2.44, 1.62 and 1.52 in order. The dose combinations shown the maximal synergism were 1870g of pyrazolate with 140g of butachlor (1:0.075), 33008 of pyrazoxyfene with 338 of pretilachlor (1:0.01), and 3350g of benzophenap with 520g of butachlor (1:0.15) on the ai/㏊ basis.

새로운 합성방법을 개발하여 pyrazolate 제초제의 곁가지를 변화시킨 새로운 구조의 3-trifluoro-methylpyrazole 유도체들과 4-benzenecarbinolpyrazole 유도체 등을 합성하여 전작과 답작상태에서 제초활성 시험을 하였다. 밭조건에서는 발아전처리의 경우 4 kg/ha의 약량에서도 제초효과를 나타내지 않았으며 발아후처리에서는 제초효과가 있었으나 미약하였다. 답작상태에서는 4 kg/ha의 약량에서 제초효과가 있었으며 특히 4-benzoylpyrazole의 benzene의 4위치에 electron-donating group인 methoxy가 치환된 화합물의 경우 활성과 선택성이 매우 좋았다. 그러나, methoxy가 두 개 이상 치환되거나 다른 electron-donating group인 sulfide기가 치환된 화합물들의 제초활성은 약하였다.

3-Trifluoromethylpyrazoles and 4-benzenecarbinolpyrazoles were prepared by the new synthetic methodologies, and their herbicidal effects were tested (in vivo) in the upland conditions and in the flooded paddy conditions for the purpose of the development of new herbicides. In upland conditions, most of the pyrazoles showed weak herbicidal effects at 4 kg/ha dosage in the post-emergence test, while no herbicidal effects in the pre-emergence test. In the flooded paddy conditions, some of the pyrazoles showed good herbicidal effects at a rate of 4 kg/ha, especially, 3-trifluoromethyl-4-(4-methoxybenzoyl)pyrazole showed the best herbicidal activity with good selectivity between rice and weeds. But other derivatives substituted with electron-donating groups such as dior trimethoxy and sulfides, and 4-benzenecarbinolpyrazoles showed weak herbicidal effects.

The condensation reactions of hippuric acid and tis furyl derivative with salicyladehydes or that of salicylhippuric acid analogues with furadehyde led to the comesponding oxazoles. These wre subsequently treated with hydrazine hydrate, hydroxylamine or subjected to alkaline hydrolysis to yield new o-hydroxyaryl or salicyl containing derivatives. 5-Substituted salicylanilides were treated with piperidine and formaldehyde in a Mannich type reaction affording the corresponding 3-(N-piperidinomethyl) salicylanilides. It was noticed that the presence of an electron donating group in in position 3 in the salicylanilide moiety decrease the mollusicidal activity.

3-Methoxycarbonylmethylene-2-oxo-1,2,3,4-tetrahydroquinoxaline(7)을 hydrazine hydrate와 반응시켜 3-hydrazinocarbonylmethylene-2-oxo-1,2,3,4-tetrahydroquinoxaline(8)을 합성하였다. 화합물 8을 alkyl (ethoxymethylene)cyanoacetate류와 반응시켜 [(quinoxalin-2-ylidene)ethanoyl]-1H-pyrazole류(9)를 합성하였고, 화합물 9b를 N-alkylaniline류와 반응시켜 N-alkyl-(quinoxalin-2-ylidene)-N-phenylethanamide류(10)를 합성하였다. 얻어진 화합물 9, 10은 용액에서 enamine 형과 methylene imine 형 사이에 토토머화 현상을 나타내었는데, 이들의 토토머비를 $^1H$ NMR 로서 측정하였다.

The reaction of 3-methoxycarbonylmethylene-2-oxo-1,2,3,4-tetrahydroquinoxaline(7) with hydrazine hydrate gave 3-hydrazinocarbonylmethylene-2-oxo-1,2,3,4-tetrahydroquinoxaline(8). The reaction of compound 8 with alkyl (ethoxymethylene)cyanoacetates gave the [(quinoxalin-2-ylidene)ethanoyl]-1H-pyra-zoles(9). The reaction of compound 9b with N-alkylanilines provided the N-alkyl-(quinoxalin-2-ylidene)-N-phenylethanamides(10). Compounds 9 and 10 showed the tautomerism between the enamine and methylene imine forms in solution. The tautomer ratios were determined by the $^1H$ NMR.

Known as a female hormone, estrogen, performs important functions, and the activities of the hormone are mediated via the estrogen receptor. The principal objective of the present study was to assess the effects of a estrogen receptor agonist in male reproductive organs. In this study, the estrogen receptor alpha agonist, PPT, was injected subcutaneously into adult male mice. The effects of PPT on the murine reproductive system were histologically assessed at 3,5, and 8 weeks after treatment. In the treatment group, reductions were observed in the weight of the body, testis and epididymis. Microscopic examination revealed a reduction in seminiferous tubular diameter in the testis, and epithelial cell height in the epididymis during the experiment. 8 weeks after treatment, spermatogenesis was not detected, nor was the lumen of the seminiferous tubules. In the fertility test, 1 week after PPT injection, the fertilizing ability of males was decreased, and on the 2nd and 3rd weeks, complete infertility was observed. In conclusion, the injection of high concentrations of PPT into adult males induced physiological changes, including infertility, and also induced morphological changes, including a reduction in the height of epithelial cells within the reproductive system.

The synthetic method of pyrazole was performed by 1,3-dipolar cycloaddition with dipolarophile instead of the reaction between diazomethane and acetylene. The cycloaddition mechanism and reactivity of 3-phenyloxadiazole derivatives with dipolarophiles was investigated. In order to investigate the mechanism and reactivity of this cycloaddition, the effect of substituents having various kinds of electron withdrawing or releasing groups were examinated. Considering the effect of substituents, an electron withdrawing group attached at the 4-carbon position in 3-phenyloxadiazole derivatives decrease the reaction rate because of the lack of electron density in oxadiazole ring. The reaction rate of 3-phenyloxadiazole derivatives with dipolarophiles were more conveniently measured using UV than using a volumetric analysis which was used before. From the result of this study, it was that the cycloaddition was found to be a first-order reaction depending upon the concentration of 3-phenyloxadiazole only.

A focused library of pyrazole-based compounds was constructed towards novel transcription factor inhibitors. Complementary hydrogen bonding interaction with b-sheet peptide structures was the basis for the design of 5-amino-3-pyrazole carboxamide scaffold. From the preliminary inhibition assay against several transcription factors, compounds 7e and 8g were identified as novel lead compounds against HIF-1a and NF-AT transcription factors, respectively.

효과적인 살충제로 pyrazole 계통의 화합물이 널리 알려졌으며, 이중에 fenpyroximate와 tebufenpyrad는 시판되고 있다. 본 연구에서는 fenpyroximate의 새로운 유도체로써 5-번 위치가 치환된 pyrazole oxime ether를 합성하였다. 본 연구의 핵심 중간체인 4-formyl-5-chloro-pyrazole 2는 ethyl acetoacetate와 methylhyazine의 축합반응으로 얻은 pyrazolone 1을 Vilsmeier-Haack chloroformylation을 통하여 합성하였다. 2에 nucleophilic aromatic substitution 반응을 하여 질소고리화합물이 5-번 위치에 도입된 pyrazole aldehyde 3a-i를 만든 후, 차레로 oxime 화합물 4a-i 그리고 oxime ether 화합물 6a-i를 각각 합성하였다. 합성된 화합물 중에서 6d는 벼멸구 (Brown Planthopper, BPH), 배추좀나방 (Diamondback Moth, DBM), 점박이응애 (Two Spotted Spider Mite, TSSM)에서 높은 활성을 보여주고 있으며, 이는 fenpyroximate의 살충활성과 비슷하였다. 본 결과는 6d가 다양한 곤충 및 응애에 대하여 효과가 우월하여 살충, 살비제로써 개발 가능성을 보여주고 있다.

The pyrazole family was discovered as effective insecticides/acaricides, and fenpyroximate and tebufenpyrad were introduced in the market. In this study, new series of pyrazole oxime ethers were designed and synthesized. The pyrazolone 1 was prepared by the condensation of ethyl acetoacetate with methylhydrazine, and then subsequently subjected to the Vilsmeier-Haack chloroformylation yielding 4-formyl-5-chloro-pyrazole 2. The nucleophilic aromatic substitution of 2 generally allowed the introduction of a wide range of heterocycles into the pyrazole ring. The resulting pyrazole aldehydes 3a-i were readily converted to the corresponding pyrazole oxime derivatives 4a-i, and subsequently to 5-substituted pyrazole oxime ether derivatives 6a-i. The screening assay results clearly show that the activities of 6d were comparable to those of fenpyroximate (6a) against BPH, DBM, and TSSM. It indicates that 6d has a potential to be developed as an insecticidal agent.

4-Arylazo-3-phenyl-5-aminopyrazoles (5a, b) and substituted hydroxythiazoles 8a, b were synthesized from the reaction of 4a, b with hydrazine hydrate and mercaptoacetic acid respectively. Compounds 5a, b and 8a, b were also obtained from coupling of 2a, b with 6 and 7, respectively. 4H-1, 4-Benzothiazine 11 was prepared from 1 and 10. The resaction of the diazonium salts 2a-c with diethyl 3-amino-2-cyanopenet-2-en-1, 5-dicarboxylate 12 was also reported.