Synthesis, biological evaluation, and physicochemical property assessment of 4-substituted 2-phenylaminoquinazolines as Mer tyrosine kinase inhibitors

The cysteine proteases, cruzain and TbrCATL (rhodesain), are therapeutic targets for Chagas disease and Human African Trypanosomiasis, respectively. Among the known inhibitors for these proteases, we have described N 4-benzyl-N 2-phenylquinazoline-2,4-diamine (compound 7 in the original publication, 1a in this study), as a competitive cruzain inhibitor (K i = 1.4 μM). Here, we describe the synthesis and biological evaluation of 22 analogs of 1a, containing modifications in the quinazoline core, and in the substituents in positions 2 and 4 of this ring. The analogs demonstrate low micromolar inhibition of the target proteases and cidal activity against Trypanosoma cruzi with up to two log selectivity indices in counterscreens with myoblasts. Fourteen compounds were active against Trypanosoma brucei at low to mid micromolar concentrations. During the optimization of 1a, structure-based design and prediction of physicochemical properties were employed to maintain potency against the enzymes while removing colloidal aggregator characteristics observed for some molecules in this series.

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“…13 C NMR (100 MHz, CDCl 3 ): δ (ppm) 161.1, 157.0, 150.2, 133.5, 126.6, 126.0, 123.1, 113.6, 58.5, 38.3, 31.5. In accordance with ref .…”

Section: Methodssupporting

confidence: 85%

Structure-Based Optimization of Quinazolines as Cruzain and TbrCATL Inhibitors

et al. 2021

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“…The remaining challenges for the next phase of optimization of this series will include monitoring of cardiotoxicity risk (hERG) and other mammalian targets that are commonly associated with adverse safety risks, particularly given the lipophilicity and basic functionality the series currently possesses and that this scaffold is often considered as promiscuous. To identify potential off-target promiscuity, a substructure search of literature was performed and revealed several compound series that possess the 4-amino 2-anilinoquinazoline substructure that inhibit, with varying potencies, human kinases, − ATPases, − and G-protein coupled receptors. − As a consequence, off-target activity, particularly those associated with safety risks, will be monitored in the future development of this compound class.…”

Section: Discussionmentioning

confidence: 99%

Optimization of 2-Anilino 4-Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity

et al. 2017

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Novel antimalarial therapeutics that target multiple stages of the parasite lifecycle are urgently required to tackle the emerging problem of resistance with current drugs. Here, we describe the optimization of the 2-anilino quinazoline class as antimalarial agents. The class, identified from publicly available antimalarial screening data, was optimized to generate lead compounds that possess potent antimalarial activity against P. falciparum parasites comparable to the known antimalarials, chloroquine and mefloquine. During the optimization process, we defined the functionality necessary for activity and improved in vitro metabolism and solubility. The resultant lead compounds possess potent activity against a multidrug resistant strain of P. falciparum and arrest parasites at the ring phase of the asexual stage and also gametocytogensis. Finally, we show that the lead compounds are orally efficacious in a 4 day murine model of malaria disease burden.

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