Department of Chemistry, COMSATS University Islamabad, Islamabad Campus, Park Road, Chak Shahzad, 45550 Islamabad, Pakistan.
Department of Chemistry, COMSATS University, Abbottabad Campus, 22060 Abbottabad, Pakistan.
Bioorg Chem. 2019 Jul;88:102946. doi: 10.1016/j.bioorg.2019.102946. Epub 2019 May 1.
An irrefutable advancement has been noted for the infectious diseases caused due to ureolytic bacteria through the development of various drugs. Keeping in mind the extremely valuable synthetic utility and medicinal significance of thiourea derivatives, synthesis of new 3-trifluoromethyl benzoic acid thiourea derivatives (3a-j) were carried out. The biological potential of all compounds in terms of antimicrobial, antioxidant, cytotoxic and antiurease activities were studied. The compounds 3a, 3c and 3i with dichloro and methoxy groups substitution on the aryl group showed significant activity against all strain of bacteria while moderate to no activity was observed in remaining compounds. Whereas the antifungal evaluation showed that all compounds were active againts C. Albican and no activity was observed against C. Prapsilosis. The cytotoxic findings revealed the non-toxic nature of these compounds as IC values of majority of the compounds are above 100 μm except for compounds 3f and 3g. In addition, these compounds exhibited better antioxidant potential as 100 μm concentration inhibited >50% reactive oxygen species (ROS) production except compounds 3e, 3f and 3j. The compound 3a proved to be the most potent urease inhibitor showing the highest enzyme % inhibition (93.1%) with IC value of 8.17 ± 0.24 µM and found more active as compare to standard followed by compound 3e (92.6%), 3h (91.6%), 3d (90.8%), 3b (90.6%) and 3f (90.0%) with their respective IC values. All the synthesized compounds were docked into the binding cavity of Urease (PDB ID: 4ubp). The most active compound 3a was also ranked as top on the docking score as it was found to show valuable interactions with the target protein along with good docking scores. Hence our results revealed that the synthesized compounds have potential to be used as potent urease inhibitors after further detailed mechanistic studies.
已经注意到，通过开发各种药物，脲解细菌引起的传染病有了不可否认的进展。考虑到硫脲衍生物具有极其宝贵的合成效用和药用意义，我们进行了新的 3-三氟甲基苯甲酸硫脲衍生物（3a-j）的合成。研究了所有化合物在抗菌、抗氧化、细胞毒性和抗尿素酶活性方面的生物潜力。具有二氯和甲氧基取代基的芳基取代的化合物 3a、3c 和 3i 对所有细菌菌株均表现出显著的活性，而其余化合物则表现出中等至无活性。抗真菌评价表明，所有化合物对 C. Albican 均有效，而对 C. Prapsilosis 则无效。细胞毒性研究表明，这些化合物的非毒性性质，因为大多数化合物的 IC 值均高于 100μm，除了化合物 3f 和 3g 之外。此外，这些化合物表现出更好的抗氧化潜力，因为 100μm 浓度抑制了 >50%的活性氧（ROS）产生，除了化合物 3e、3f 和 3j 之外。化合物 3a 被证明是最有效的尿素酶抑制剂，其酶抑制率最高（93.1%），IC 值为 8.17±0.24µM，比标准品更有效，其次是化合物 3e（92.6%）、3h（91.6%）、3d（90.8%）、3b（90.6%）和 3f（90.0%），它们的 IC 值分别为 8.17±0.24µM。所有合成的化合物都被对接进入尿素酶的结合腔（PDB ID：4ubp）。最有效的化合物 3a 的对接评分也排名最高，因为它被发现与靶蛋白有有价值的相互作用，同时也有良好的对接评分。因此，我们的结果表明，这些合成的化合物在进一步详细的机制研究后，有可能作为有效的尿素酶抑制剂使用。
