16499-57-3Relevant articles and documents
Synthesis and Biological Evaluation of Quinazolonethiazoles as New Potential Conquerors towards Pseudomonas Aeruginosa
Wang, Jie,Battini, Narsaiah,Ansari, Mohammad Fawad,Zhou, Cheng-He
, p. 1093 - 1103 (2021)
Novel quinazolonthiazoles were designed and synthesized as new potential antimicrobial agents by facile multi-step procedure from o-aminobenzoic acids and 2-acetylthiazole. A series of biological evaluation showed that compound 7d was the most effective quinazolonethiazole with superior activity to reference drugs chloramphenicol and norfloxacin. This active molecule displayed unobvious bacterial resistance against P. aeruginosa, the low toxicity to normal hepatocytes, suitable pharmacokinetics and drug-likeness. The preliminary biological interaction suggested that quinazolonethiazole 7d might induce bacterial death by disturbing the membrane permeability, whilst preventing bacteria from growth by integrating into DNA and binding with topoisomerase IV. These findings provided significant background for the further development of quinazolonethiazoles as new potential drugs in combating drug-resistant pathogens.
Identification of Unique Quinazolone Thiazoles as Novel Structural Scaffolds for Potential Gram-Negative Bacterial Conquerors
Wang, Jie,Ansari, Mohammad Fawad,Zhou, Cheng-He
, p. 7630 - 7645 (2021)
A class of quinazolone thiazoles was identified as new structural scaffolds for potential antibacterial conquerors to tackle dreadful resistance. Some prepared compounds exhibited favorable bacteriostatic efficiencies on tested bacteria, and the most representative 5j featuring the 4-trifluoromethylphenyl group possessed superior performances against Escherichia coli and Pseudomonas aeruginosa to norfloxacin. Further studies revealed that 5j with inappreciable hemolysis could hinder the formation of bacterial biofilms and trigger reactive oxygen species generation, which could take responsibility for emerging low resistance. Subsequent paralleled exploration discovered that 5j not only disintegrated outer and inner membranes to induce leakage of cytoplasmic contents but also broke the metabolism by suppressing dehydrogenase. Meanwhile, derivative 5j could intercalate into DNA to exert powerful antibacterial properties. Moreover, compound 5j gave synergistic effects against some Gram-negative bacteria in combination with norfloxacin. These findings indicated that this novel structural type of quinazolone thiazoles showed therapeutic foreground in struggling with Gram-negative bacterial infections.
Development of a Robust Scale-Up Synthetic Route for BPR1K871: A Clinical Candidate for the Treatment of Acute Myeloid Leukemia and Solid Tumors
Reddy, Julakanti Satyanarayana,Chen, Chih-Ming,Coumar, Mohane Selvaraj,Sun, Hsu-Yi,Sun, Na,Hsieh, Hsing-Pang
, p. 817 - 830 (2021)
Herein, a robust and scalable procedure for the synthesis of multikinase inhibitor BPR1K871 (1, a quinazoline compound bearing a substituted thiazoline side chain), which is a clinical candidate for the treatment of acute myeloid leukemia and solid tumors, is reported. The previously reported medicinal chemistry synthetic route A with seven steps had encountered several issues during scale-up syntheses such as low yields (7.7% overall yield), the formation of inseparable impurities, particularly in the chlorination step, use of hazardous reagents (NaH/DMF), and laborious column chromatography steps for the purification of the products. A step-by-step approach to overcome the above issues was planned and implemented through two similar routes (B1 and B2) on a gram scale and finally through route B3 on a kilogram scale to synthesize 1. The final optimized synthetic route B3 does not require column chromatography purification steps. It is one step shorter than the original route A and avoided hazardous reagents for the alkylation reaction in step 2. Furthermore, the highlights of the new route B3 include liquid-liquid continuous extraction of compound 13 in step 2, the use of POCl3 instead of SOCl2 to minimize the formation of impurities in the chlorination step 3, and telescoped synthesis of key Boc-protected amino intermediate 15 from 13, in high purity. Using the scale-up route B3, the final product 1 (3.09 kg, yield of 16.5% over six steps with an HPLC purity of 97.8%) was obtained in a single batch for preclinical testing and facilitated clinical testing of 1, which is underway.
Discovery of BPR1R024, an Orally Active and Selective CSF1R Inhibitor that Exhibits Antitumor and Immunomodulatory Activity in a Murine Colon Tumor Model
Chang, Chun-Yu,Chen, Chiung-Tong,Chou, Ling-Hui,Hsieh, Hsing-Pang,Huang, Yu-Chen,Lai, You-Liang,Lee, Kun-Hung,Lin, Wen-Hsing,Shih, Chuan,Su, Yu-Chieh,Wang, Pei-Chen,Wu, Cai-Syuan,Yang, Chen-Ming,Yeh, Teng-Kuang,Yen, Wan-Ching
supporting information, p. 14477 - 14497 (2021/10/20)
Colony-stimulating factor-1 receptor (CSF1R) is implicated in tumor-associated macrophage (TAM) repolarization and has emerged as a promising target for cancer immunotherapy. Herein, we describe the discovery of orally active and selective CSF1R inhibitors by property-driven optimization of BPR1K871 (9), our clinical multitargeting kinase inhibitor. Molecular docking revealed an additional nonclassical hydrogen-bonding (NCHB) interaction between the unique 7-aminoquinazoline scaffold and the CSF1R hinge region, contributing to CSF1R potency enhancement. Structural studies of CSF1R and Aurora kinase B (AURB) demonstrated the differences in their back pockets, which inspired the use of a chain extension strategy to diminish the AURA/B activities. A lead compound BPR1R024 (12) exhibited potent CSF1R activity (IC50 = 0.53 nM) and specifically inhibited protumor M2-like macrophage survival with a minimal effect on antitumor M1-like macrophage growth. In vivo, oral administration of 12 mesylate delayed the MC38 murine colon tumor growth and reversed the immunosuppressive tumor microenvironment with the increased M1/M2 ratio.
