Natural Compound-derived Cytochrome bc1 Complex Inhibitors as Antifungal Agents

Abstract

The high incidence of fungal pathogens has become a global issue for crop protection. A promising strategy to control fungal plant infections is based on the use of nature-inspired compounds. The cytochrome bc1 complex is an essential component of the cellular respiratory chain and is one of the most important fungicidal targets. Natural products have played a crucial role in the discovery of cytochrome bc1 inhibitors, as proven by the development of strobilurins, one of the most important classes of crop-protection agents, over the past two decades. In this review, we summarize advances in the exploration of natural product scaffolds for the design and development of new bc1 complex inhibitors. Particular emphasis is given to molecular modeling-based approaches and structure-activity relationship (SAR) studies performed to improve the stability and increase the potency of natural precursors. The collected results highlight the versatility of natural compounds and provide an insight into the potential development of nature-inspired derivatives as antifungal agents.

Keywords: (E)-β-methoxyacrylate; antifungals; cytochrome bc1 complex; natural compounds; strobilurins.

Figure 1

Schematic model of cytochrome bc1 complex. The homodimeric bc1 complex presents three catalytic subunits: cytochrome b (cyt b) with two b-type haems (b_H and b_L), the Rieske iron–sulfur protein (FeS) and cytochrome c1 (cyt c1) with one c-type haem. The two binding sites for inhibitors and ubiquinone (UQ), Qi and Qo, are shown. The bifurcated electron transfer pathway from the Qo site is shown by red arrows.

Figure 2

Structure of natural strobilurin A and B, and the methoxyacrylate stilbene (MOAS) lead structure.

Figure 3

Commercial strobilurins.

Figure 4

Structural optimization of lead compound 13 and inhibitory activities of representative compounds 14a–14d and azoxystrobin (AZ) against porcine SCR (succinate cytochrome c reductase) with cytochrome c as substrate.

Figure 5

Enoxastrobin-inspired analogs.

Figure 6

Structure of strobilurin derivatives containing a triazole moiety (20–25) and structure of azoxystrobin analog 26.

Figure 7

Structure of representative coumoxystrobin analogs 28–30 containing the quinolin-2(1H)-one moiety.

Figure 8

Structure of 3,4-dichloroisothiazole and 1,2,3-thiadiazole-containing strobilurins.

Figure 9

Structure of representative compounds and EC₅₀ values against Sclerotinia sclerotiourum (azoxystrobin EC₅₀ = 18.75 ± 1.10 mg/L) [EC₅₀ values from Reference [31]].

Figure 10

Structure of pyraclostrobin analogs from Reference [33].

Figure 11

Structure of pyraclostrobin analogs from Reference [34].

Figure 12

Structure of strobilurin analogs containing hydrazono-methyl moiety.

Figure 13

Structure of strobilurins analogs containing the tetrazolinone pharmacophore (46–48).

Figure 14

Structure of natural cyrmenins and analogs.

Figure 15

Structures of mixothiazols, melithiazols, and fulvuthiacens.

Figure 16

Structures of miuraenamides A-F (66–71) and related derivatives (72–75).

Figure 17

Structures of crocacins A–D (76–79) and stigmatellin A (80).

Figure 18

Structure of neopeltolide (88) and representative simplified analogs (89, 90a,b and 91).

Figure 19

Structures of natural tocopherols (α, β, γ-, and δ-Toc, 92–95), of tocopheryl quinones (α, β, γ -, and δ-TQ, 96–99), and low molecular weight analogs (100 and 101).

Figure 20

Karrikinolide (102) and selected derivatives 103a–d from Reference [59].

Figure 21

Structure of natural picolinamide UK-2A (104), of fenpicoxamid (105), and structures of representative analogs (106–108).