El-Tombary Alaa A
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Alexandria, Alexandria 21521, Egypt.
Sci Pharm. 2013 Apr-Jun;81(2):393-422. doi: 10.3797/scipharm.1211-21. Epub 2013 Jan 7.
In the present investigation, some new pyrazolo[3,4-d]pyrimidin-4(5H)-one derivatives (7-12) as well as fused pyrazolo[3',4':4,5]pyrimido[1,2-b]pyridazin-4(1H)-one (14-16) and 7,8,9,10-tetrahydropyrazolo[3',4':4,5]pyrimido[1,2-b]-cinnolin-4(1H)-one (17) ring systems were synthesized using the starting compound 5-amino-6-methyl-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (5). The structures of the newly synthesized compounds were elucidated by IR, (1)H NMR, (13)C NMR, mass spectroscopy, and elemental analysis. The theoretical calculation of their lipophilicity as C log P was performed. The anti-inflammatory activity of all newly synthesized compounds was evaluated using the carrageenan-induced paw edema test in rats using indomethacin as the reference drug. Ulcer indices for the most active compounds were calculated. Seven compounds (10b, 11a-f) showed consistently good anti-inflammatory activity. In particular, 5-{[4-(4-bromophenyl)-3-(4-chlorophenyl)-1,3-thiazol-2(3H)-ylidene]amino}-6-methyl-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (11e) and its 3,4-bis(4-chlorophenyl) analog (11f) were found to be the most effective among the other derivatives, showing activity comparable to that of indomethacin with minimal ulcerogenic effects. Correlation of the biological data of the active compounds with their theoretically calculated C log P values revealed that lipophilicity influences the biological response.
在本研究中，以起始化合物5-氨基-6-甲基-1-苯基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮（5）合成了一些新的吡唑并[3,4-d]嘧啶-4(5H)-酮衍生物（7-12）以及稠合的吡唑并[3',4':4,5]嘧啶并[1,2-b]哒嗪-4(1H)-酮（14-16）和7,8,9,10-四氢吡唑并[3',4':4,5]嘧啶并[1,2-b]噌啉-4(1H)-酮（17）环系。通过红外光谱、¹H核磁共振、¹³C核磁共振、质谱和元素分析对新合成化合物的结构进行了阐明。对它们的亲脂性进行了理论计算，以C log P表示。以吲哚美辛作为参比药物，采用角叉菜胶诱导大鼠足爪肿胀试验对所有新合成化合物的抗炎活性进行了评价。计算了活性最强的化合物的溃疡指数。七种化合物（10b、11a-f）始终表现出良好的抗炎活性。特别地，发现5-{[4-(4-溴苯基)-3-(4-氯苯基)-1,3-噻唑-2(3H)-亚基]氨基}-6-甲基-1-苯基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮（11e）及其3,4-双(4-氯苯基)类似物（11f）在其他衍生物中最为有效，显示出与吲哚美辛相当的活性且致溃疡作用最小。活性化合物的生物学数据与其理论计算的C log P值之间的相关性表明，亲脂性影响生物学反应。
