Tolprocarb | Fungicides I Polyketide Synthase Enzyme (PKS) Inhibitors

Tolprocarb [2,2,2-Trifluoroethyl-N-[(1S)-2-methyl-1-[[(4-methylbenzoyl)amino]methyl]propyl carbamate] is a novel new member of group of compounds that specifically block melanin biosynthesis in the pathogen, commonly referred to as conventional melanin biosynthesis inhibitors (cMBIs). It is developed as a fungicide to act against Magnaporthe grisea, the causal agent of rice blast. The novelty of Tolprocarb lies in its new and unique mechanism of action against the pathogen, which overcomes any form of resistance that pathogen, might have against the existing cMBIs.

Tolprocarb: 2D and 3D Structure

Tolprocarb is developed and launched by Mitsui Chemicals in 2012 with focus on the rice market, where Tolprocarb shows good control of Magnaporthe grisea.

Mechanism for Activity

Rice blast caused by Magnaporthe grisea is a major fungal disease affecting rice production worldwide. In its infection process, M. grisea produces unicellular infection structures, called appressoria, which adhere tightly to the host surface and produce slender infection pegs that pierce the underlying cell wall of the host. The cell wall of appressoria contains a dense layer of 1,8-dihydroxynaphthalene (1,8-DHN)-melanin synthesized from 1,8-DHN. The accumulation of the dark-colored 1,8-DHN-melanin between the plasma membrane and the cell wall is an essential step before the appressoria of Magnaporthe and other fungal species can penetrate host plants.

It is also known that 1,8-DHN-melanin-deficient mutants of M. grisea, which cannot produce the dark gray pigment typical of wildtype mycelia failed to infect intact host plants.

In various fungal species (e.g., M. grisea, etc), biochemical analysis of enzymes involved in the melanin biosynthetic pathway has been reported.

The biosynthetic pathway for melanin in fungi starts from pentaketide synthesis and cyclization to form 1,3,6,8-tetrahydroxynaphthalene (1,3,6,8-THN) by polyketide synthase (PKS). The subsequent steps entail reduction of 1,3,6,8-THN to scytalone, dehydration of scytalone to 1,3,8-trihydroxynaphthalene (1,3,8-THN), reduction of 1,3,8-THN to vermelone, and dehydration of vermelone to 1,8-dihydroxynaphthalene (1,8-DHN). 1,8-DHN is then polymerized and oxidized to yield melanin [1].

While other cMBIs such as tricyclazole, pyroquilon, carpropamid, diclocymet are known to inhibit either reductase or dehydratase enzymes in the melanin biosynthesis pathway, Tolprocarb is unique in that it inhibits the polyketide synthase enzyme (PKS).

Developer

Tolprocarb is developed and launched as a fungicide by Mitsui Chemicals in 2012. Tolprocarb showed a high controlling effect on rice blast by both nursery box application and broadcasting on paddy rice, and its practical value has been verified.

Reported Activities for Tolprocarb

IC₅₀ (Inhibition of polyketide synthase activity) = 0.03 uM

IC₉₀ (Inhibition of polyketide synthase activity) = 0.23 uM

Summary

Common name: Tolprocarb; MTF-0301; MTF0301; MTF 0301

Trademarks: -

Molecular Formula: C16H21F3N2O3

CAS Registry Number: 911499-62-2

CAS Name: (S)-2,2,2-trifluoroethyl (3-methyl-1-(4-methylbenzamido)butan-2-yl)carbamate

Molecular Weight: 346.34

SMILES: FC(F)(COC(N[C@@H](C(C)C)CNC(C1=CC=C(C)C=C1)=O)=O)F

InChI Key: RSOBJVBYZCMJOS-CYBMUJFWSA-N

InChI: InChI=1S/C16H21F3N2O3/c1-10(2)13(21-15(23)24-9-16(17,18)19)8-20-14(22)12-6-4-11(3)5-7-12/h4-7,10,13H,8-9H2,1-3H3,(H,20,22)(H,21,23)/t13-/m1/s1

Mechanism of Action: Polyketide Synthase Enzyme (PKS) Inhibitors

Activity: Fungicide

Status: Launched 2012 (Japan)

Chemical Class: Flourine Containing; Tri-Flouro Molecules; Amides; Small-molecules; L-valine containing; Amino acid containing

Originator: Mitsui Chemicals

Tolprocarb Synthesis

WO2012039132A1: The patent reports synthesis for Tolprocarb and its various derivatives. The synthesis starts with condensation between trifluoroethyl chloroformate and L-valine. The carbamate thus obtained is then treated sequentially with phosgene and ammonia to yield carboxamide, which is again reacted with phosgene to afford the nitrile intermediate. Palladium catalyzed hydrogenation of cyano-intermediate, followed by amidation and reaction with activated 4-methylbenzoic acid, yields Tolprocarb in 75% overall yield.

Identifications:

1H NMR (Estimated) for Tolprocrab

Experimental: ¹H NMR (CDCl₃) δ 0.96-1.03 (6H, m), 1.85-1.91 (1H, m), 2.39 (3H, s), 3.46-3.51 (1H, m), 3.61-3.72 (2H, m) , 4.35-4.46 (2H, m), 5.26 (1H, d, J = 8.30Hz), 6.62 (1H, brs), 7.21-7.23 (2H, m), 7.63-7.65 (2H, m).

Adverse Reports:

Nothing available.

Others:

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References:

1. Hamada, T.; et. al. Action mechanism of the novel rice blast fungicide tolprocarb distinct from that of conventional melanin biosynthesis inhibitors. J Pestic Sci 2014, 39(3), 152-158. (free article)

2. Umetani, H.; et. al. Method for producing amino acid amide derivative having fluorine-containing carbamate group, production intermediate thereof, and method for producing ethylene diamine derivative. WO2012039132A1

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