Küçükgüzel S Güniz, Mazi Adil, Sahin Fikrettin, Oztürk Suzan, Stables James
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Istanbul 81010, Turkey.
Eur J Med Chem. 2003 Nov-Dec;38(11-12):1005-13. doi: 10.1016/j.ejmech.2003.08.004.
Several diflunisal hydrazide-hydrazone derivatives namely 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid [(5-nitro-2-furyl/substitutedphenyl)methylene] hydrazide (3a-o) have been synthesised. Methyl 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylate (1) and 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid hydrazide (2) were also synthesised and used as intermediate compounds. All synthesised compounds were screened for their antimycobacterial activity against Mycobacterium tuberculosis H37 Rv, antimicrobial activities against various bacteria, fungi and yeast species. Compound 3a have shown activity against Staphylococcus epidermis HE-5 and Staphylococcus aureus HE-9 at 18.75 and 37.5 microg mL(-1), respectively. Compound 3o have exhibited activity against Acinetobacter calcoaceticus IO-16 at a concentration of 37.5 microg mL(-1), whereas Cefepime, the drug used as standard, have been found less active against the microorganisms mentioned above. The synthesised compounds were found to provide 12-34% inhibition of mycobacterial growth of M. tuberculosis H37 Rv in the primary screen at 6.25 microg mL(-1). Anticonvulsant activity of the compounds were also determined by maximal electroshock (MES) and subcutaneous metrazole (scMET) tests in mice and rats following the procedures of antiepileptic drug development (ADD) program of the National Institutes of Health (NIH). Compound 3k showed 25% protection against MES induced seizures in p.o. rat screening at a dose level of 30 mg kg(-1) whereas 3n and 3o showed neurotoxicity after 4 and 0.5 h at a dose level of 100 and 300 mg kg(-1), respectively.
已合成了几种二氟尼柳酰肼腙衍生物，即2',4'-二氟-4-羟基联苯-3-羧酸[(5-硝基-2-呋喃基/取代苯基)亚甲基]肼(3a-o)。还合成了2',4'-二氟-4-羟基联苯-3-羧酸甲酯(1)和2',4'-二氟-4-羟基联苯-3-羧酸酰肼(2)并用作中间体化合物。对所有合成化合物针对结核分枝杆菌H37 Rv的抗分枝杆菌活性、针对各种细菌、真菌和酵母菌种的抗菌活性进行了筛选。化合物3a分别在18.75和37.5μg mL(-1)浓度下对表皮葡萄球菌HE-5和金黄色葡萄球菌HE-9表现出活性。化合物3o在37.5μg mL(-1)浓度下对醋酸钙不动杆菌IO-16表现出活性，而用作标准药物的头孢吡肟对上述微生物的活性较低。在6.25μg mL(-1)的初筛中，发现合成化合物对结核分枝杆菌H37 Rv的分枝杆菌生长有12-34%的抑制作用。还按照美国国立卫生研究院(NIH)的抗癫痫药物开发(ADD)计划的程序，通过小鼠和大鼠的最大电休克(MES)和皮下注射戊四氮(scMET)试验测定了化合物的抗惊厥活性。化合物3k在口服大鼠筛选中，在30 mg kg(-1)剂量水平下对MES诱导的惊厥表现出25%的保护作用，而化合物3n和3o分别在100和300 mg kg(-1)剂量水平下，在4小时和0.5小时后表现出神经毒性。
