New pyrazole derivative 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole: synthesis and assessment of some biological activities

The molecular modification and synthesis of compounds is vital to discovering drugs with desirable pharmacological and toxicity profiles. In response to pyrazole compounds' antipyretic, analgesic, and anti‐inflammatory effects, this study sought to evaluate the analgesic, anti‐inflammatory, and vasorelaxant effects, as well as the mechanisms of action, of a new pyrazole derivative, 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole. During the acetic acid‐induced abdominal writhing test, treatments with 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole reduced abdominal writhing, while during the formalin test, 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole reduced licking times in response to both neurogenic pain and inflammatory pain, all without demonstrating any antinociceptive effects, as revealed during the tail flick test. 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole also reduced carrageenan‐induced paw edema and cell migration during the carrageenan‐induced pleurisy test. As demonstrated by the model of the isolated organ, 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole exhibits a vasorelaxant effect attenuated by Nω‐nitro‐l ‐arginine methyl ester, 1H‐[1,2,4]oxadiazolo[4,3‐alpha]quinoxalin‐1‐one, tetraethylammonium or glibenclamide. 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole also blocked CaCl₂‐induced contraction in a dose‐dependent manner. Suggesting a safe toxicity profile, 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole reduced the viability of 3T3 cells at higher concentrations and was orally tolerated, despite signs of toxicity in doses of 2000 mg/kg. Lastly, the compounds' analgesic activity might be attributed to the involvement of the NO/cGMP pathway and K⁺ channels observed in the vasorelaxant effect.     

Structure Activity Relationship of Antiproliferative Agents using Multiple Linear Regression

With cancer‐related fatalities being the second leading cause of death in the USA, understanding the activity of effective chemotherapeutic agents is critical to addressing prostate and other cancers. Celecoxib, an FDA‐approved drug for the treatment of colon tumors, has been used successfully as a lead compound in the development of antiproliferative agents. The ability of celecoxib to inhibit the development and progression of tumors has been connected to a number of mechanisms of actions that are both dependent on and independent of its cyclooxygenase‐2 activity. A structure‐based approach has been employed to develop a model that underscores the structural significance of celecoxib as an antiproliferative agent. By evaluating the structure activity of this library of molecules, we were able to create a QSAR model for predicting the antiproliferative activity of structurally similar molecules. The development of the model will be presented in this paper.     

Brain imaging of mechanically induced muscle versus cutaneous pain

Cerebrovascular disorders are less common in pre-menopausal than post-menopausal women and in females than males. This protection may be due, in part at least, to direct effects of oestrogens on blood vessels. Oestrogen's vasodilatory mechanisms have been reported to be via the endothelium, vascular smooth muscle and extracellular matrix, depending on the vascular bed studied. Herein we investigated the vasoactive effects of oestrogen, oestrogen receptor (ER) and GPR30 agonists and selective ER modulators (SERMs) in the rat middle cerebral artery(MCA), an artery affected in focal ischaemia.MCAs isolated from male Sprague Dawley rats were mounted on a wire myograph. Concentration response curves were constructed to 17β-oestradiol, ERα agonist-PPT, ERβ agonist-DPN, GPR30 agonist-G1 and novel SERMs (LY362321 and LY2120310) in pre-constricted vessels, in the presence and absence of endothelium, blocking agents for nitric oxide synthase (L-NAME), classic ER antagonist (ICI182,780) or plasma membrane specific ERα (ERα-36) antibody.17β-oestradiol induced rapid vasorelaxation of the MCA which was not affected by endothelium removal, L-NAME or ICI182,780. Vasorelaxation was mimicked by PPT, DPN and G1 but not by the SERMs. Using ERα-36 antibody, effects of oestrogen were partially blocked. PPT had a greater vasorelaxation, while DPN and G1 had a lesser effect than 17β-oestradiol. These findings indicate that activation of plasma membrane bound ERα, β and GPR30 elicits rapid, endothelial-nitric oxide-independent relaxation of the rat MCA.     

探讨复方托吡卡胺在儿童屈光检查中的应用价值

目的探讨复方托吡卡胺在儿童屈光检查的应用价值探讨。方法需要屈光检查的儿童同时采用复方托吡卡胺和阿托品散瞳用药后屈光检查,以阿托品散瞳检影验光的远视屈光度为标准值,并比较两者的屈光差异。结果复方托吡卡散瞳验光110眼总屈光度低于阿托品散瞳验光总屈光度者95眼,占86.36%,低幅为0.25～1.25D,平均每眼低0.63D;复方托吡卡胺散瞳验光总屈光度高于阿托品散瞳验光总屈光度者13眼,占11.82%,高幅为0.25～0.75D,平均每眼高0.50D;相同者2眼,占1.82%。结论复方托吡卡胺散瞳验光总屈光度与阿托品散瞳验光总屈光度接近,在配眼镜时考虑这些因素,可以替代阿托品散瞳减少患儿的散瞳后各种不适。     

1,3,5-三取代吡唑类ALK5抑制剂的合成与生物评价研究

目的 设计合成1,3,5-三取代吡唑类化合物,并研究其对ALK5所介导的TGFβ信号通路的抑制活性,以期发现新型ALK5抑制剂。方法 先以取代的苯甲醛和4-乙酰苯甲腈为原料,合成取代的查儿酮,再与芳基肼或芳基肼盐酸盐反应生成1,3,5-三取代吡唑啉,然后氧化脱氢得到相应的1,3,5-三取代吡唑类化合物,最后对官能团做适当的变换,得到目标化合物。应用基于细胞的TGF-Smad2 检测评价了化合物的ALK5抑制活性。结果与结论 合成目标化合物29个,其结构均经过了核磁与质谱的确证,其中化合物6c显示有较好的ALK5抑制活性。     

Anti-inflammatory and anti-tumor activity of the marine mangrove Rhizophora apiculata

A methanolic extract of Rhizophora apiculata was evaluated for its anti-inflammatory and anti-tumor activity against B16F10 melanoma cells in BALB/c mice. The administration of R. apiculata extract was shown to inhibit the solid tumor development in mice. R. apiculata treatment significantly reduced tumor cell glutathione (GSH) levels as well as serum γ-glutamyl transpeptidase (GGT) and nitric oxide (NO) levels in the tumor-bearing animals. The total white blood cell count and hemoglobin levels were also significantly increased in extract-treated hosts. The use of R. apiculata substantially reduced the acute inflammation (assessed as paw edema) induced by carrageenan and also reduced inflammation edema induced by formalin. Analysis of this methanolic extract revealed a high content of 4-pyrrolidinyl, pyrazole, and ketone derivatives. These studies suggest that R. apiculata extract could be used as a (natural) anti-inflammatory and anti-tumor agent.     

4(5)-Aryl-2-C-glucopyranosyl-imidazoles as New Nanomolar Glucose Analogue Inhibitors of Glycogen Phosphorylase

d-Glucopyranosyl) isoxazole, pyrazole, thiazole, and imidazole type compounds were synthesized, and the latter showed the strongest inhibition against rabbit muscle glycogen phosphorylase b. Most efficient was 2-(β-d-glucopyranosyl)-4(5)-(2-naphthyl)-imidazole (11b, K_i = 31 nM) representing the best nanomolar glucose derived inhibitor of the enzyme.     

Synthesis of new bis‐pyrazole linked hydrazides and their in vitro evaluation as antimicrobial and anti‐biofilm agents: A mechanistic role on ergosterol biosynthesis inhibition in Candida albicans

Literature reports suggest that pyrazoles and hydrazides are potential antimicrobial pharmocophores. Considering this fact, a series of nineteen conjugates containing hybrids of bis‐pyrazole scaffolds joined through a hydrazide linker were synthesized and further evaluated for their antimicrobial activity against a panel of Gram‐positive and Gram‐negative bacteria along with Candida albicansMTCC 3017 strain. Although the derivatives exhibited good antibacterial activity, some of the derivatives ( 13d , 13j , 13l , 13p , and 13r ) showed excellent anti‐Candida activity with MICs values of 3.9 μg/ml, which was equipotent to that of the standard Miconazole (3.9 μg/ml), which has inspired us to further explore their anti‐Candida activity. The same compounds were also tested for anti‐biofilm studies against various Candida strains and among them, compounds 13l and 13r efficiently inhibited the formation of fungal biofilms. Field emission scanning electron micrographs revealed that one of the promising compound 13r showed cell damage and in turn cell death of the Candida strain. These potential conjugates ( 13l and 13r ) also demonstrated promising ergosterol biosynthesis inhibition against some of the strains C. albicans, which were further validated through molecular docking studies. In silico computational studies were carried out to predict the binding modes and pharmacokinetic parameters of these conjugates.