Department of Pharmaceutical Chemistry, GITAM Institute of Pharmacy, Rushikonda, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, 530045, India.
Antiinflamm Antiallergy Agents Med Chem. 2021;20(2):182-195. doi: 10.2174/1871523019999201116191622.
Due to the presence of both five-membered heterocyclics like pyrrole and thiophene in one molecule considerable attention was made for their enormous pharmacological activities out of which include anti-inflammatory and anti-ulcer activities.
Chalcones with toluenesulfonylmethyl isocyanide (TosMIC) undergo synthesis to form some new aryl (4-aryl-1H-pyrrol-3-yl) (thiophen-2-yl) methanone derivatives. Molecular docking of synthesized compounds with protein receptors of anti-inflammatory COX-1(3N8Y), COX-2 (1PXX) along with anti-ulcer H+/K+ATPase enzyme (2XZB) followed with drug-likeness, and in silico ADMET properties.
The multicomponent reaction was carried out by the intermediate formation of α, β-unsaturated ketone from carbonyl compounds which on sequential addition undergoes [3+2] cycloaddition reaction in same medium affords aryl (4-aryl-1H-pyrrol-3-yl) (thiophen-2-yl) methanone derivatives by addition of TosMIC in basic medium had resulted in series of compounds PY1 to PY12. All the new synthesized compounds were screened for their in-vitro anti-inflammatory activity by bovine serum albumin method followe with COX assay, and in-vivo by using carrageenan-induced rat paw edema method of the selected compounds PY1, PY5 and PY12 which is also screened for anti-ulcer activity by pylorus ligation method, respectively. Molecular docking was performed using autodock tools, drug-likeness by OSIRIS property explorer and admetSAR properties.
From the synthesized compounds of aryl (4-aryl-1H-pyrrol-3-yl) (thiophen- 2-yl) methanone derivatives PY5 showed decent in-vitro and in-vivo anti-inflammatory along selectivity index of 6.2 for COX-1 with IC50(μM) value of 9.54 over diclofenac with 8.74 and PY1 showed decent in-vivo anti-ulcer activities along with drug-likeness and in silico ADMET predictions revealed that all the synthesized compounds have minimal toxic effects with good absorption as well as solubility characteristics. The selected compounds may serve as potential lead compounds for developing new anti-inflammatory and anti-ulcer drugs.
From the newly synthesized molecules PY5 was found to be effective for anti-inflammatory and PY1 was found to be effective for anti-ulcer activities further derivitization and designed of modification to achieve more compounds with potent anti-inflammatory and anti-ulcer activities.
由于一个分子中同时存在五元杂环如吡咯和噻吩，因此它们具有巨大的药理学活性，其中包括抗炎和抗溃疡活性，引起了相当大的关注。
用甲苯磺酰甲基异氰化物（TosMIC）合成查尔酮，形成一些新的芳基（4-芳基-1H-吡咯-3-基）（噻吩-2-基）甲酮衍生物。对合成化合物与抗炎 COX-1（3N8Y）、COX-2（1PXX）的蛋白受体以及抗溃疡 H+/K+ATP 酶（2XZB）进行分子对接，然后进行药物相似性和计算机 ADMET 特性分析。
通过羰基化合物中间形成α，β-不饱和酮进行多组分反应，然后在同一介质中连续添加进行[3+2]环加成反应，在碱性介质中加入 TosMIC 得到芳基（4-芳基-1H-吡咯-3-基）（噻吩-2-基）甲酮衍生物，通过该方法得到一系列化合物 PY1 到 PY12。所有新合成的化合物均通过牛血清白蛋白法进行体外抗炎活性筛选，然后进行 COX 测定，通过角叉菜胶诱导的大鼠足肿胀法进行体内抗炎活性筛选，选择化合物 PY1、PY5 和 PY12 进行抗溃疡活性筛选，分别采用幽门结扎法进行筛选。采用 autodock tools 进行分子对接，采用 OSIRIS property explorer 进行药物相似性分析，采用 admetSAR properties 进行 ADMET 预测。
从芳基（4-芳基-1H-吡咯-3-基）（噻吩-2-基）甲酮衍生物的合成化合物中，PY5 表现出良好的体外和体内抗炎活性，选择性指数为 6.2，对 COX-1 的 IC50（μM）值为 9.54，优于双氯芬酸的 8.74，PY1 表现出良好的体内抗溃疡活性，具有药物相似性和计算机 ADMET 预测，表明所有合成化合物的毒性作用最小，具有良好的吸收和溶解度特性。所选化合物可能成为开发新型抗炎和抗溃疡药物的潜在先导化合物。
从新合成的分子中发现 PY5 对抗炎有效，PY1 对抗溃疡有效，进一步进行衍生化和设计修饰，以获得更多具有更强抗炎和抗溃疡活性的化合物。
