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1.
Bioorg Med Chem ; 35: 116073, 2021 04 01.
Article in English | MEDLINE | ID: mdl-33610010

ABSTRACT

Streptochlorin is a small molecule of indole alkaloid isolated from marine Streptomyces sp., it is a promising lead compound due to its potent bioactivity in preventing many phytopathogens in our previous study, but further structural modifications are required to improve its antifungal activity. Our work in this paper focused on the replacement of oxazole ring in streptochlorin with the imidazole ring, to discover novel analogues. Based on this design strategy, three series of streptochlorin analogues were efficiently synthesized through sequential Vilsmeier-Haack reaction, Van Leusen imidazole synthesis and halogenation reaction. Some of the analogues displayed excellent activity in the primary assays, and this is highlighted by compounds 4g and 4i, the growth inhibition against Alternaria Leaf Spot and Rhizoctorzia solani under 50 µg/mL are 97.5% and 90.3%, respectively, even more active than those of streptochlorin, pimprinine and Osthole. Molecular docking models indicated that streptochlorin binds with Thermus thermophiles Leucyl-tRNA Synthetase in a similar mode to AN2690, offering a perspective on the mode of action study for antifungal activities of streptochlorin derivatives. Further study is still ongoing with the aim of discovering synthetic analogues, with improved antifungal activity and clear mode of action.


Subject(s)
Alternaria/drug effects , Antifungal Agents/pharmacology , Drug Design , Indoles/pharmacology , Molecular Docking Simulation , Oxazoles/pharmacology , Rhizoctonia/drug effects , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Dose-Response Relationship, Drug , Indoles/chemical synthesis , Indoles/chemistry , Microbial Sensitivity Tests , Molecular Structure , Oxazoles/chemical synthesis , Oxazoles/chemistry , Structure-Activity Relationship
2.
Mol Divers ; 25(1): 205-221, 2021 Feb.
Article in English | MEDLINE | ID: mdl-32056130

ABSTRACT

Based on the strategy of diversity-oriented synthesis and the structures of natural product pimprinine and streptochlorin, two series of novel pimprinine derivatives containing 1,3,4-oxadiazole-5-thioether moieties were efficiently synthesized under the optimized reaction conditions. Biological assays conducted at Syngenta showed the designed derivatives displayed an altered pattern of biological activity, of which 5h was identified as the most promising compound with strong activity against Pythium dissimile and also a broad antifungal spectrum in primary screening. Further structural optimization of pimprinine and streptochlorin derivatives is well under way, aiming to discover synthetic analogues with improved antifungal activity. Two series of novel pimprinine derivatives containing 1,3,4-oxadiazole-5-thioether moieties were efficiently synthesized through diversity-oriented synthesis strategy under the optimized conditions. Biological assays showed the designed derivatives exhibited potential activity.


Subject(s)
Antifungal Agents/chemical synthesis , Oxadiazoles/chemistry , Oxazoles/chemistry , Sulfides/chemistry , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Biological Products/chemistry , Biological Products/pharmacology , Indoles/chemistry , Microbial Sensitivity Tests/methods , Pythium/drug effects , Structure-Activity Relationship
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