Discovery of N-Methoxy-(biphenyl-ethyl)-pyrazole-carboxamides as Novel Succinate Dehydrogenase Inhibitors

Abstract

Succinate dehydrogenase (SDH) inhibitor is one of the research hotspots for the development of fungicides. Herein, we describe the design and synthesis of N-methoxy-(biphenyl-ethyl)-pyrazole-carboxamide derivatives with enhanced fungicidal activity by employing fragment combination strategy. The SDH enzymatic activity was evaluated for 24 title compounds, and compound 7s was identified as the highest activity against porcine SDH with an IC50 value of 0.014 μM, 205-fold greater than that of fluxapyroxad. Furthermore, the greenhouse experiments showed that compound 7u exhibited potent fungicidal activity against wheat powdery mildew with an EC50 value of 0.633 mg/L, higher activity than fluxapyroxad and benzovindiflupyr. The computational results showed that the fluorine atom substituted on the pyrazole ring formed an extra dipolar–dipolar interaction with C_S42 and then increased the van der Waals interaction between the compound and SDH. The structural and mechanistic insights obtained from the present work will provide a valuable clue to developing novel SDH inhibitors.

Structure-Based Discovery of New Succinate Dehydrogenase Inhibitors via Scaffold Hopping Strategy

“…To further enhance the activity of inhibitors, we optimized X 2 on the pyrazole scaffold. In our previous study, we found that replacing hydrogen in the pyrazole ring with fluorine could increase the potency of the compounds. , Therefore, compounds G27 – G42 with a fluorine atom on the pyrazole ring were synthesized. Compared to hydrogen-substituent compounds, these fluorine-substituent compounds displayed remarkable enhanced inhibition potency, with IC 50 values essentially reaching several tens of nanomolar levels, such as compounds G28 (4-Cl, IC 50 = 26.00 nM), G33 (4-Br, IC 50 = 31.00 nM), G34 (4-OCF 3 , IC 50 = 77.00 nM), G35 (4-CF 3 , IC 50 = 48.00 nM), and G40 (2-F-4-Cl, IC 50 = 27.00 nM).…”

“… a Δ G exp = −RT ln IC 50 . b Obtained from ref . c R 2 is the correlation coefficient between Δ G exp and other energy terms. …”

“…In our previous work, the stretched amide linker in pydiflumetofen was scaffolded into the chemical structure of fluxapyroxad and designed a series of N-methoxy-(biphenylethyl)-pyrazole-carboxamide derivatives, which showed better control effects against WPM and CPM than fluxapyroxad, and slightly less than pydiflumetofen at 0.78 mg/L dosage. 23 These results indicated that prolonging the amide bond linker was a valid strategy to obtain novel SDHIs. Here, to continue our previous work, gem-dichloralkene obtained from benzovindiflupyr were scaffolded hopping into the stretched amide linker in pydiflumetofen (Figure 2).…”

Bioactivity-Guided Subtraction of MIQOX for Easily Available Isoquinoline Hydrazides as Novel Antifungal Candidates

“…To this point, our continuing efforts were attracted by the discovery of novel antifungal ligands based on coenzyme Q itself (e.g., drimane hydroquinones) − as well as the rational design (e.g., aryloxazoline) inspired by coenzyme Q binding pockets. The chemical variation of SDHIs has received increasing attention for the discovery and development of new antifungal leads. ,− The structural diversity has been significantly advanced owing to the merit of a specially designed scaffold. Our research group has been a contributor in this area since 2016 with aryloxazoline as a special model in view of its chemical and biological insights (Figure A).…”

Discovery of Novel Pyrazol-5-yl-benzamide Derivatives Containing a Thiocyanato Group as Broad-Spectrum Fungicidal Candidates

“… − In recent years, various effective strategies, such as scaffold hopping, bioisosterism, and pharmacophore-linked fragment virtual screening (PFVS) methods, have been employed to optimize pyrazole-4-carboxamides. These strategies have led to the discovery of many SDHIs with distinct structures. − According to the cocrystal structure of SDH from the porcine heart, it was observed that the polar segment could be embedded into the ubiquinone binding site, thus resulting in a higher binding affinity for SDHIs. Consequently, the modification of the pyrazole skeleton in a pyrazole-4-carboxamide structure is a promising tactic for the development of novel SDHI fungicides with a higher activity and broader spectrum. ,, …”