A series of 3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives were designed and synthesized. Structure-activity relationship (SAR) analysis of these compounds led to the discovery of compound 1j, which showed the highest inhibitory potency against the Src kinase and the most potent antiviability activity against the typical TNBC cell line MDA-MB-231 among all the synthesized compounds. Further kinase inhibition assays showed that compound 1j was a multikinase inhibitor and potently inhibited Src (IC50 = 0.0009 μM) and MAPK signaling protein kinases B-RAF and C-RAF. In an MDA-MB-231 xenograft mouse model, a once-daily dose of compound 1j at 30 mg/kg for 18 days completely suppressed the tumor growth with a tumor inhibition rate larger than 100% without obvious toxicity. It also displayed good pharmacokinetic properties in a preliminary pharmacokinetic assay. Western blot and immunohistochemical assays revealed that compound 1j significantly inhibited Src and MAPK signaling and markedly induced apoptosis in tumor tissues.

This paper describe the structural optimization of a hit compound, N2-(4-(4-methylpiperazin-1-yl)phenyl)-N8-phenyl-9H-purine-2,8-diamine (1), which is a reversible kinase inhibitor targeting both EGFR-activating and drug-resistance (T790M) mutations but has poor binding affinity. Structure-activity relationship studies led to the identification of 9-cyclopentyl-N2-(4-(4-methylpiperazin-1-yl)phenyl)-N8-phenyl-9H-purine-2,8-diamine (9e) that exhibits significant in vitro antitumor potency against the non-small-cell lung cancer (NSCLC) cell lines HCC827 and H1975, which harbor EGFR-activating and drug-resistance mutations, respectively. Compound 9e was further assessed for potency and selectivity in enzymatic assays and in vivo anti-NSCLC studies. The results indicated that compound 9e is a highly potent kinase inhibitor against both EGFR-activating and resistance mutations and has good kinase spectrum selectivity across the kinome. In vivo, oral administration of compound 9e at a dose of 5 mg/kg caused rapid and complete tumor regression in a HCC827 xenograft model, and an oral dose of 50 mg/kg initiated a considerable antitumor effect in an H1975 xenograft model.

Gray mold, caused by Botrytis cinerea, is one of the most destructive fungal diseases in crops, responsible for significant economic losses. In search of natural product-based fungicides, we designed and synthesized a series of novel 3,4dichlorophenyl isoxazole-substituted stilbene derivatives, and their in vivo antifungal activities against B. cinerea were evaluated. The results indicated that some of the target molecules demonstrated remarkable efficiency for the control of tomato gray mold. In particular, compound 5r displayed the highest fungicidal potency with an inhibition rate of 56.11% comparable to that of positive control boscalid (66.96%). Moreover, a hologram quantitative structure−activity relationship (HQSAR) model with good predictive capability was developed to provide in-depth insight into the activity profiles of these compounds. Preliminary mechanism studies suggested that compound 5r might exert its antifungal effect by changing hyphal morphology and increasing the membrane permeability. The present study contributes to the development of natural stilbene derivatives as alternative bioactive agents against B. cinerea.

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BACKGROUND: The emergence of drug-resistant phytopathogenic bacteria and the need for new types of biological diseasecontrol agents have accelerated efforts toward searching for alternative candidates with a low propensity for resistance development. In this study, a new series of stilbene-based peptoid mimics were synthesized, and their biological activities were evaluated against citrus pathogenic bacteria in vitro and in vivo. RESULTS: Antibacterial bioassay results showed that the dicationic peptoid mimics 9a and 9b displayed excellent bioactivity against Xanthomonas citri pv. citri, with the minimum inhibitory concentration values of 25 ∼M, which were superior to those of commercial copper biocides Delite (200 ∼M) and Kasumin Bordeaux (100 ∼M). In vivo bioassay further confirmed their control efficacy against plant bacterial diseases. In addition, the antibacterial mechanism of action elucidated their membranedisruption effects resulting in the leakage of the bacterial membranes, which was similar to that of antimicrobial peptides. Moreover, the inhibition effect on biofilm formation of peptoid mimics has also been demonstrated. CONCLUSION: Stilbene-based peptoid mimics synthesized in this study showed promising antibacterial activity with a potent membrane-disruptive mechanism. The results suggested that stilbene-based peptoid mimics have the potential as a candidate new type of bactericide for citrus disease protection.