Aggarwal Shilpy, Paliwal Deepika, Kaushik Dhirender, Gupta Girish Kumar, Kumar Ajay
R.K.S.D (PG) College, Kaithal, Haryana, India.
Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra 136119, India.
Comb Chem High Throughput Screen. 2018;21(3):194-203. doi: 10.2174/1386207321666180213092911.
Malaria is one of the most vital infectious diseases caused by protozoan parasites of the Plasmodium genus. As P. falciparum, the cause of most of the severe cases of malaria, is increasingly resistant to available drugs such as amodioquine, chloroquine, artemisinin, and antifolates, there is an urgent need to identify new targets for chemotherapy.
This study screened novel pyrazole derivatives carrying iminium & benzothiazole group for antimalarial potential against P. falciparum chloroquine sensitive (3D7) strain.
MATERIALS & METHODS: Several pyrazole schiff base hybrids with a wide range of substitution have been synthesized via condensation of substituted aniline with substituted 4-formylpyrazole and evaluated for their in vitro antimalarial activity against asexual blood stages of human malaria parasite, Plasmodium falciparum. The interaction of these conjugate hybrids was also investigated by molecular docking studies in the binding site of P. falciparum cystein protease falcipain-2. The pharmacokinetic properties were also studied using ADME prediction.
Among all compounds, 6bf and 6bd were found to be potential molecules with EC50 1.95µg/ml and 1.98µg/ml respectively. Docking study results reveal that the pyrazole schiff base derivatives occupy the PfFP binding sites and they show good interactions with significant values of binding energies.
We provide evidence which implicates pyrazole Schiff base hybrids as potential prototypes for the development of antimalarial agents.
疟疾是由疟原虫属原生动物寄生虫引起的最重要的传染病之一。由于导致大多数严重疟疾病例的恶性疟原虫对可用药物如氨酚喹、氯喹、青蒿素和抗叶酸药物的耐药性日益增强，迫切需要确定新的化疗靶点。
本研究筛选了带有亚胺鎓和苯并噻唑基团的新型吡唑衍生物对恶性疟原虫氯喹敏感（3D7）株的抗疟潜力。
通过取代苯胺与取代4-甲酰基吡唑的缩合反应合成了几种具有广泛取代基的吡唑席夫碱杂化物，并对其针对人类疟原虫恶性疟原虫无性血液阶段的体外抗疟活性进行了评估。还通过分子对接研究在恶性疟原虫半胱氨酸蛋白酶恶性疟原虫蛋白酶-2的结合位点研究了这些共轭杂化物的相互作用。还使用ADME预测研究了药代动力学性质。
在所有化合物中，发现6bf和6bd是潜在分子，其EC50分别为1.95μg/ml和1.98μg/ml。对接研究结果表明，吡唑席夫碱衍生物占据PfFP结合位点，并且它们显示出良好的相互作用以及具有显著的结合能值。
我们提供的证据表明吡唑席夫碱杂化物作为抗疟药物开发的潜在原型。
