Bukvić Krajacić Mirjana, Novak Predrag, Cindrić Mario, Brajsa Karmen, Dumić Miljenko, Kujundzić Nedjeljko
PLIVA-Research and Development Ltd., Prilaz baruna Filipovića 29, Zagreb, Croatia.
Eur J Med Chem. 2007 Feb;42(2):138-45. doi: 10.1016/j.ejmech.2006.08.008. Epub 2006 Sep 28.
Novel hybrid compounds 6a-6d, conjugates of 15-membered azalides and sulfonamides, i.e. unsubstituted, 4-aryl- and 4-heteroaryl-aminosulfonyl derivatives of 9a-[N'-(phenylcarbamoyl)]-9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A were synthesized and characterized by IR, one- and two-dimensional NMR spectroscopies and MALDI-TOF and MS/MS mass spectrometry. The new compounds were evaluated in vitro against a panel of sensitive and resistant Gram-positive and Gram-negative bacterial strains. 9a-{N'-[4-(Aminosulfonyl)phenyl]carbamoyl}--(6a) and 9a-{N'-[4-(phenylaminosulfonyl)phenyl]carbamoyl}--(6b) derivatives showed improvements in activity against inducible resistant Streptococcus pyogenes in comparison with macrolide antibiotic azithromycin and starting material 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A (2). In addition, the synthesized azithromycin-sulfonamide conjugates 6a-6d showed good antibacterial activity against sensitive S. pyogenes and Streptococcus pneumoniae strains. The kinetics of degradation in the artificial gastric juice showed that the most active compounds, 6a and 6b, exhibited azithromycin like stability. The cleavage of the cladinose sugar was found to be the main decomposition pathway leading to inactive 7a and 7b, prepared also as analytical standards by the alternative synthetic route together with 7c and 7d.
新型杂合化合物6a - 6d，即15元氮杂内酯与磺酰胺的缀合物，也就是9a - [N' -（苯基氨基甲酰基）]-9 - 脱氧-9 - 二氢-9a - 氮杂-9a - 高红霉素A的未取代、4 - 芳基和4 - 杂芳基氨基磺酰基衍生物，通过红外光谱、一维和二维核磁共振光谱以及基质辅助激光解吸电离飞行时间质谱和串联质谱进行了合成与表征。对这些新化合物针对一系列敏感和耐药的革兰氏阳性及革兰氏阴性细菌菌株进行了体外评估。与大环内酯类抗生素阿奇霉素和起始原料9 - 脱氧-9 - 二氢-9a - 氮杂-9a - 高红霉素A（2）相比，9a - {N' - [4 -（氨基磺酰基）苯基]氨基甲酰基}-（6a）和9a - {N' - [4 -（苯基氨基磺酰基）苯基]氨基甲酰基}-（6b）衍生物对诱导型耐药化脓性链球菌的活性有所提高。此外，合成的阿奇霉素 - 磺酰胺缀合物6a - 6d对敏感的化脓性链球菌和肺炎链球菌菌株显示出良好的抗菌活性。在人工胃液中的降解动力学表明，活性最高的化合物6a和6b表现出类似阿奇霉素的稳定性。发现克拉定糖的裂解是导致无活性的7a和7b的主要分解途径，7a和7b也通过替代合成路线制备为分析标准品，同时还制备了7c和7d。
