Kaur Navpreet, Korkor Constance, Mobin Shaikh M, Chibale Kelly, Singh Kamaljit
Department of Chemistry, Centre of Advanced Study, Guru Nanak Dev University, Amritsar, 143005, India.
Department of Chemistry, Indian Institute of Technology Indore Simrol, Khandwa Road, Indore, 453552, India.
ChemMedChem. 2022 Oct 6;17(19):e202200414. doi: 10.1002/cmdc.202200414. Epub 2022 Sep 15.
Fluorene-chloroquine hybrids have been identified as a new promising class of antiplasmodial agents. The most active compound 9 d exhibited good in vitro antiplasmodial activity against a chloroquine-sensitive NF54 strain of the human malaria parasite Plasmodium falciparum with an IC value of 139 nM. UV-visible absorption, FTIR spectral and H NMR titration data corroborated the binding of 9 d to monomeric and μ-oxodimeric heme as well as inhibition of β-hematin formation, which collectively supported the inhibition of heme detoxification machinery in P. falciparum. In silico docking studies revealed the binding interactions of the hybrids in the active site of the wild type as well as quadruple mutant of Pf-DHFR-TS dihydrofolate enzyme. Further, the ADMET parameters were predicted and were in good agreement with the expected values, suggesting the drug likeness of the synthesized hybrid molecules.
芴-氯喹杂化物已被确认为一类新的有前景的抗疟原虫药物。活性最高的化合物9 d对氯喹敏感的人类疟原虫恶性疟原虫NF54菌株表现出良好的体外抗疟原虫活性，IC值为139 nM。紫外可见吸收光谱、傅里叶变换红外光谱和核磁共振氢谱滴定数据证实了9 d与单体和μ-氧代二聚体血红素的结合以及对β-血红素形成的抑制，这共同支持了对恶性疟原虫血红素解毒机制的抑制。计算机对接研究揭示了这些杂化物在野生型以及Pf-DHFR-TS二氢叶酸酶四重突变体的活性位点中的结合相互作用。此外，预测了ADMET参数，且与预期值吻合良好，表明合成的杂化分子具有药物相似性。
