Identification of 5-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine as novel orally bioavailable and metabolically stable antimalarial compound for further exploration,Chemical Biology & Drug Design

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Identification of 5-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine as novel orally bioavailable and metabolically stable antimalarial compound for further exploration
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2022-11-02 , DOI: 10.1111/cbdd.14170
Mrinalkanti Kundu ₁ , Aditi Dutta ₁ , Kuldeep K Roy ₂ , Sajal K Mal ₁ , Shouvik Karmakar ₁ , Aritra Mandal ₁ , Susanta K Mondal ₁ , Sanjay Kumar ₁ , Soumya Saha ₁ , Subhankar Pradhan ₁ , Ratul Sarkar ₁ , Monali Chakrabarti ₁ , Pradip K Malik ₁ , Manish Banerjee ₁

Affiliation

Malaria continues to be a significant public health problem threatened by the emergence and spread of resistance to artemisinin-based combination therapies and marked half a million deaths in 2016. A new imidazopyridine chemotype has been envisaged through scaffold-hopping approach combined with docking studies for putative-binding interactions with Plasmodium falciparum phosphatidylinositol-4-kinase (PfPI4K) target. The docking results steered to the synthesis of compound 1 [5-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine] followed by the in vitro screening for antiplasmodial activity and ADME-PK studies. Combined with potent antimalarial activity of compound 1 (Pf3D7 IC₅₀ = 29 nM) with meager in vitro intrinsic clearance, moderate plasma-protein binding, and acceptable permeability, compound 1 displayed sustained exposure and high oral bioavailability in mice and can thus have the potential as next generation PI4K inhibitor for in vivo studies.

中文翻译：

鉴定 5-(3-(甲基磺酰基)苯基)-3-(4-(甲基磺酰基)苯基)-3H-咪唑并[4,5-b]吡啶作为新型口服生物利用度和代谢稳定的抗疟化合物以供进一步探索

疟疾仍然是一个重大的公共卫生问题，受到对青蒿素联合疗法耐药性的出现和传播的威胁，并在 2016 年造成 50 万人死亡。通过支架跳跃方法结合对接研究设想了一种新的咪唑并吡啶化学型-与恶性疟原虫磷脂酰肌醇 4 激酶 ( Pf PI4K) 靶点的结合相互作用。对接结果指导化合物1 [5-(3-(甲基磺酰基)苯基)-3-(4-(甲基磺酰基)苯基)-3 H-咪唑并[4,5- b ]吡啶]的合成，随后是抗疟原虫活性的体外筛选和 ADME-PK 研究。结合化合物的强效抗疟活性1 ( Pf 3D7 IC ₅₀ = 29 nM) 具有微弱的体外固有清除率、适度的血浆蛋白结合和可接受的渗透性，化合物1在小鼠中表现出持续暴露和高口服生物利用度，因此具有作为下一代 PI4K 抑制剂的潜力体内研究。

更新日期：2022-11-02

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