作者: Abd El-Lateef, Hany M. ; El-Faham, Ayman ; Hamid, Malai Haniti S. A. ; Aljamhi, Waleed A. ; Barakat, Assem ; Z Arfan, Nur Hazimah B. ; Sheikh, Nadeem S. ; Shawish, Ihab ; Hammud, Hassan H.

The corrosion inhibition of C-steel by two s-triazine/morpholino-anilino-pyrazole derivatives, namely, 4-(3,5-dimethyl-1H-pyrazol-1-yl)-6-morpholino-N-phenyl-1,3,5-triazin-2-amine (1) and N-(4-bromophenyl)-4-(3,5-dimethyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-amine (2) was investigated by impedimetric and potentiometric studies. It was found that (1) and (2) acted as cathodic-type corrosion inhibitors that retard the hydrogen evolution reaction. The percent corrosion inhibition, 98.5% for compound (2) (with bromo substituent) at 80 ppm, was slightly higher than 97.8% for (1) at 100 ppm. Thus, the replacement of a -H with -Br substituent increased the corrosion inhibition properties. Compound (2) exhibited Temkin isotherm adsorption, whereas compound (1) exhibited Langmuir adsorption. Scanning electron microscopy (SEM) analysis of the steel surface indicated that the inhibitors caused protection of the surface. The weight loss experiment also proved the decrease in the corrosion rate when inhibitors were added. The difference in inhibitory efficiency between compounds (1) and (2) was investigated by density functional theory (DFT) to study neutral and protonated species in gaseous and aqueous phases. The theoretical analysis demonstrated that compound (2) exhibited higher inhibitory activity on a metal surface compared to compound (1), aligning with the experimental results. The energy associated with the metal/adsorbate arrangement, represented by dE _ads/dN_i , was higher for (2) (-380.91 kcal mol^-1) compared to (1) (-371.64 kcal mol^-1). This indicated better adsorption of (2) over (1).

2023-10-11·Journal of agricultural and food chemistry

Discovery of Benzothiazolylpyrazole-4-Carboxamides as Potent Succinate Dehydrogenase Inhibitors through Active Fragment Exchange and Link Approach.

Article

作者: Sun, Zong-Yue ; Yin, Yan-Ming ; Wang, Da-Wei ; Xi, Zhen

Succinate dehydrogenase (SDH) is an attractive target for developing green fungicides to manage agricultural pathogens in modern agriculture research. Herein, in this work, we report the discovery of benzothiazolylpyrazole-4-carboxamides I-III as potent SDH inhibitors using active fragment exchange and link approach. The results of the fungicidal activity assays showed that some of the synthesized compounds exhibited excellent inhibition against the tested fungi. Systematic structure-activity relationship studies led to the discovery of compound Ip, N-(1-((4,6-difluorobenzo[d]thiazol-2-yl)thio)propan-2-yl)-3-(difluoromethyl)-N-methoxy-1-methyl-1H-pyrazole-4-carboxamide, which showed higher fungicidal activity against Fusarium graminearum Schw (EC₅₀ = 0.93 μg/mL) than the commercial fungicides thifluzamide (EC₅₀ > 50 μg/mL) and boscalid (EC₅₀ > 50 μg/mL). The molecular simulation studies suggested that hydrophobic interactions were the primary driving forces between ligands and SDH. Promisingly, we found that Ip could stimulate the growth of wheat seedlings and Arabidopsis thaliana and increase the biomass of the treated plants. Preliminary studies on the plant growth promoter mechanism of Ip indicated that it could increase nitrate reductase activity in planta, that, in turn, stimulates the growth of plants.

2021-10-14·Journal of Medicinal Chemistry1区 · 医学

Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (AZD5305): A PARP1–DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs

1区 · 医学

Article

作者: Degorce, Sébastien L. ; Varnes, Jeffrey G. ; Zhang, Ke ; Xue, Lin ; Bista, Michal ; McWilliams, Lisa ; Lane, Jordan ; Pachl, Fiona ; She, Hongyao ; Ghosh, Avipsa ; Talbot, Verity ; Hemsley, Paul ; Cosulich, Sabina ; Embrey, Kevin ; Larner, Carrie ; Edmondson, Scott D. ; Fawell, Stephen ; Liu, Lina ; Critchlow, Susan E. ; Illuzzi, Giuditta ; Zhang, Andrew X. ; Packer, Martin J. ; Johannes, Jeffrey W. ; Chuba, Matthew D. ; Staniszewska, Anna D. ; Di Fruscia, Paolo ; Hande, Sudhir M. ; Pike, Andrew ; Barratt, Derek ; Heightman, Tom D. ; Zheng, Xiaolan ; Martin, Scott ; Pei, Xiaohui ; Madin, Andrew ; Underwood, Elizabeth ; Orme, Jonathan P. ; Leo, Elisabetta ; Gunnarsson, Anders ; Gill, Sonja J. ; O’Connor, Mark J. ; Schimpl, Marianne ; Balazs, Amber ; Yao, Tieguang

Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1-DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of 25 (AZD5305), a potent and selective PARP1 inhibitor and PARP1-DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25 is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.

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