Design, synthesis and biological evaluation of new 2-aminothiazole scaffolds as phosphodiesterase type 5 regulators and COX-1/COX-2 inhibitors.
Design, synthesis and biological evaluation of new 2-aminothiazole scaffolds as phosphodiesterase type 5 regulators and COX-1/COX-2 inhibitors.
复制标题
新的2-氨基硫唑支架作为5型调节剂和COX-1/COX-2抑制剂的设计，合成和生物学评估。
作者：
设计并制备了一系列新的2-氨基噻唑衍生物，作为磷酸二酯酶5型（PDE5）调节剂和COX-1/COX-2抑制剂。以西地那非为参比药物，对合成化合物进行PDE5活性筛选。值得注意的是，化合物23a和23c在10 μM时对PDE5具有完全抑制作用（100%），而不会引起低血压，并且PDE5抑制剂的副作用有限，这表明这些衍生物在勃起功能障碍中具有独特的治疗作用。另一方面，化合物5a、17、21和23b在10 μM处增加PDE5活性（PDE5增强剂）。此外，本研究还包括筛选合成的化合物对COX-1/COX-2的抑制作用。所有化合物对COX-1活性（IC50 = 1.00 ~ 6.34 μM）和COX-2活性（IC50 = 0.09 ~ 0.71 μM）均有抑制作用。此外，通过分子对接研究揭示了强效化合物在PDE5 （PDB ID）、COX-1和COX-2 （PDB ID）酶结合位点的结合相互作用。对于与PDE5酶的相互作用，激活剂化合物比抑制衍生物具有较强的结合模式（HB与Gln817: a）。这两种化合物都被认为是PDE5调节剂。这一新发现将鼓励我们发现一种新的药理应用小化学实体作为PDE5增强剂，或将降低PDE5抑制剂的副作用。所有活性化合物沿COX-2活性位点均呈y型。设计并制备了一系列新的2-氨基噻唑衍生物，作为磷酸二酯酶5型（PDE5）调节剂和COX-1/COX-2抑制剂。
A new series of 2-aminothiazole derivatives was designed and prepared as phosphodiesterase type 5 (PDE5) regulators and COX-1/COX-2 inhibitors. The screening of the synthesized compounds for PDE5 activity was carried out using sildenafil as a reference drug. Strikingly, compounds 23a and 23c were found to have a complete inhibitory effect on PDE5 (100%) at 10 μM without causing hypotension and the limited side effect of PDE5 inhibitors, suggest a distinctive therapeutic role of these derivatives in erectile dysfunction. On the other hand, compounds 5a, 17, 21 and 23b increased the PDE5 activity (PDE5 enhancers) at 10 μM. In addition, the study includes the screening of the COX-1/COX-2 inhibition induced by the synthesized compounds. All tested compounds have an inhibitory effect against COX-1 activity (IC50 = 1.00–6.34 μM range) and COX-2 activity (IC50 = 0.09–0.71 μM range). Moreover, a molecular docking study was implemented to reveal the binding interactions of potent compounds in the binding sites of PDE5 (PDB ID ), COX-1 and COX-2 (PDB ID ) enzymes. For the interaction with the PDE5 enzyme, activator compounds had a strong binding mode (HB with Gln817:A) than inhibitory derivatives. Both types of compounds are considered as PDE5 regulators. This novel finding will encourage us to discover a new pharmacological application of small chemical entities as the PDE5 enhancer, or will lower side effects as PDE5 inhibitors. All active compounds adopted the Y-shape along the COX-2 active site. A new series of 2-aminothiazole derivatives was designed and prepared as phosphodiesterase type 5 (PDE5) regulators and COX-1/COX-2 inhibitors.
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影响因子：
2.9
作者：
Zhang, Li;Zhang, Zhenggang;Chopp, Michael
通讯作者：
Chopp, Michael
影响因子：
4.8
作者：
Wang L;Burmeister BT;Johnson KR;Baillie GS;Karginov AV;Skidgel RA;O'Bryan JP;Carnegie GK
通讯作者：
Carnegie GK
影响因子：
3.5
作者：
Morelli, Annamaria;Filippi, Sandra;Maggi, Mario
通讯作者：
Maggi, Mario
影响因子：
3.5
作者：
Elshaier, Yaseen A. M. M.;Shaaban, Mohamed A.;Halaweish, Fathi
通讯作者：
Halaweish, Fathi
影响因子：
2.1
作者：
Hussein, Abdel Haleem M.;El-Adasy, Abu-Bakr A.;Abdel-Rady, Mohamed
通讯作者：
Abdel-Rady, Mohamed