Streptochlorin analogues as potential antifungal agents: Design, synthesis, antifungal activity and molecular docking study.

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.

An Improved Process for the Preparation of an α,α-Difluorosulfonylisoxazoline Herbicide.

An efficient synthesis of a difluorosulfone-containing herbicide has been achieved by selective reductive silylation of a symmetrical bis(trifluoromethyl)-1,2,3-triazole. Subsequently, a fluoride-induced reaction led to a difluoromethyl anion equivalent, which was reacted with a sulfur electrophile leading ultimately to the key difluorosulfide moiety.

Synthesis and antifungal activity of novel indole-replaced streptochlorin analogues.

Based on examples of the successful applications in drug discovery of bioisosterism, a series of streptochlorin analogues in which indole has been replaced by other heterocycles has been designed and synthesized, as a continuation of our studies aimed at the discovery of novel streptochlorin analogues with improved antifungal activity. Biological testing showed that most of the indole-replaced streptochlorin analogues were inactive, though compound 6f had a broad spectrum of antifungal activity with significant activity against Alternaria solani. The SAR study demonstrated that indole ring is an essential moiety for the antifungal activity of streptochlorin analogues, promoting the idea of indole ring as a framework that might be exploited in the future.

Synthesis and antifungal activity of novel streptochlorin analogues.

Streptochlorin, first isolated as a new antibiotic in 1988 from the lipophilic extracts of the mycelium of a Streptomyces sp, is an indole natural products with a variety of biological activities. Based on the methods developed for the synthesis of pimprinine in our laboratory, we have synthesized a series of indole-modified streptochlorin analogues and measured their activities against seven phytopathogenic fungi. Some of the analogues displayed good activity in the primary assays, and the seven compounds 10b, 10c, 11e, 13e, 21, 22c and 22e (shown in Figure 1) were identified as the most promising candidates for further study. Structural optimization is still ongoing with the aim of discovering synthetic analogues with improved antifungal activity.

Synthesis and antifungal activity of 3-(1,3,4-oxadiazol-5-yl)-indoles and 3-(1,3,4-oxadiazol-5-yl)methyl-indoles.

On the basis of the principle of combination of active structural moieties, a modified and efficient synthetic method for three series of novel indole-based 1,3,4-oxadiazoles is described. Bioassays conducted at Syngenta showed that several of the synthesized compounds exhibit higher antifungal activity than pimprinine, the natural product which inspired this synthesis. Two main structural alterations were found to broaden the spectrum of biological activity in most cases. Compounds 3g, 6c, 6e, 6h, 9d, 9e, 9h and 9m (Fig. 1) were identified as the most active on the biological assays, and will be studied further.

Synthesis and antifungal activity of novel sclerotiorin analogues.

Sclerotiorin 1, first isolated from Penicillium sclerotiorum, has weak antifungal activity and belongs to the azaphilone-type family of natural products. Several series of sclerotiorin analogues were designed and synthesized with the aim of discovering novel fungicides with improved activity. The syntheses involved two key steps, cycloisomerization and then oxidation, and used a simple and efficient Sonogashira cross-coupling reaction to construct the required functionalized precursor. With sclerotiorin as a control, the activities of the newly synthesized analogues were evaluated against seven fungal pathogens, and several promising candidates (compounds 3a1, 3d2, 3e2, 3f2 and 3k2) with greater activity and simpler structures than sclerotiorin were discovered. In addition, preliminary structure-activity relationships were studied, which revealed that not only the chlorine or bromine substituent at the 5-position of the nucleus but also the phenyl group at the 3-position and the substituent pattern on it contributed crucially to the observed antifungal activity. Analogues with a methyl substituent at the 1-position have reduced levels of activity, while those with a free hydroxyl group in place of acetoxy at the quaternary center of the bicyclic ring system retain activity.

Design, synthesis and fungicidal activity of novel sclerotiorin derivatives.

Sclerotiorin, a chlorine-containing azaphilone-type natural product, was first isolated from Penicillium sclerotiorum and has been reported to exhibit weak fungicidal activity. Optimization of the substituents at the 3- and 5-positions of the sclerotiorin framework was investigated with the aim of discovering novel fungicides with improved activity. The design of sclerotiorin analogues involved replacing the diene side chain with a phenyl group or an aromatic- or heteroaromatic-containing aliphatic side chain. The designed compounds were synthesized by cycloisomerization and subsequent oxidation of suitable 2-alkynylbenzaldehydes, in which a variety of substituents were introduced using a Sonogashira coupling reaction. The structures of these newly prepared compounds were confirmed by 1H and 13C NMR spectroscopy, HRMS and single-crystal X-ray analysis. The antifungal activity of the synthesized compounds was evaluated against seven phytopathogenic species. Compounds 3, 9g and 9h were found to have a broad spectrum of fungicidal activity, and these structurally simpler products can be recognized as lead compounds for further optimization.

Synthesis and fungicidal activity of novel pimprinine analogues.

A simple and efficient synthetic protocol for 5-(3-indolyl)-oxazoles has been developed and further used to synthesize a series of novel analogues of natural product pimprinine. All new compounds were identified by (1)H NMR, high resolution mass spectrometry, and the structures of 10 and 18o were further confirmed by X-ray crystallographic diffraction analysis. Bioassay conducted at Syngenta showed that several of the synthesized compounds exhibited fungicidal activity. Compounds 10, 17, 18 h, 18o, 19 h, 19i and 19 l all showed effective control of three out of the seven tested phytopathogenic fungi at the highest rate screened. Compounds 17 and 19 h in particular showed activity against the four pathogens screened in artificial media; Pythium dissimile, Alternaria solani, Botryotinia fuckeliana and Gibberella zeae.