Expedient discovery of novel oxime ester derivatives of piperine/piperine analogs as potent pesticide candidates and their mode of action against Tetranychus cinnabarinus Boisduval

Abstract

BACKGROUNDNowadays, pest infestation and resistance have appeared as a consequence of repeated and extensive use of pesticides. Thus, development of new effective pesticide candidates in crop protection is highly desirable. Herein, a series of new piperine derivatives containing oxime ester scaffolds were regioselectively and stereoselectively prepared as pesticidal agents.RESULTSSteric configurations of compounds 2, 5z and 13e were definitively determined by single‐crystal X‐ray diffraction. Against Tetranychus cinnabarinus, notably, compounds 5f [median lethal concentration (LC50) = 0.14 mg mL−1] and 5v (LC50 = 0.13 mg mL−1) showed >107‐fold greater acaricidal activity than piperine (LC50 = 15.02 mg mL−1), which were comparable to the commercial acaricide spirodiclofen. Against Aphis citricola, compound 5d (LD50 = 19.12 ng aphid−1) exhibited 6.1‐fold more potent aphicidal activity than piperine (LD50 = 116.06 ng aphid−1). Additionally, through scanning electron microscopy, the toxicology study suggested that the acaricidal activity of piperine derivatives may be related to damage of the cuticle layer crest of T. cinnabarinus.CONCLUSIONThe structure–activity relationships suggested that 3,4‐dioxymethylene of piperine was crucial for its acaricidal activity; and introduction of a certain length of aliphatic chain at the C‐2 position was beneficial to the aphicidal and acaricidal activities. Compounds 5f and 5v are potential leads for further structural modification as acaricidal agents. © 2023 Society of Chemical Industry.

Piperine: Chemistry and Biology

“…As described in Scheme 1 and Scheme 2 , Li et al and Lv et al regio- and stereo-selectively synthesized a series of piperine-type ester derivates 23a – 23z and 23a’ – 23l’ , and oxime ester derivates 25a – 25z and 25a’ – 25h’ , respectively, by using the Vilsmeier–Haack–Arnold (VHA) reaction. Meanwhile, as shown in Scheme 3 , by changing the substituent groups of dioxymethylene ring, compounds 33a – 33i were also prepared by Lv et al All the synthetic compounds were evaluated for their acaricidal activities against T. cinnabarinus, among them, compounds 23e , 23f , 23u , 23v , 25f , 25l , 25u , and 25v showed significant acaricidal activities with the LC 50 values ranging from 0.12 to 0.19 mg/mL ( Table 1 ), which were comparable to that of the commercial acaricidal agent spirodiclofen (LC 50 : 0.12 mg/mL), and displayed almost 100-fold higher acaricidal activities than piperine (LC 50 : 14.20 mg/mL) [ 28 , 29 , 60 ]. As shown in Scheme 4 , Gu et al used the catalyst RhH-1 to reduce the aliphatic olefin chain of piperine under a mild condition with a high yield to obtain analogue 34 [ 61 ].…”

“…Replacing the dioxymethylene ring with a 2-oxazoline heterocyclic ring and introducing a Cl atom at the C-10 position can produce an anti-inflammatory agent, which has potent therapeutic effects against neuroinflammation [ 46 ]; (ii) introduction of ester and oxime ester groups at C-2 position of piperine is important for improving acaricidal activity. In particular, the long aliphatic chain esters or oxime esters, and a very crucial prerequisite is to retain the dioxymethylene ring [ 28 , 29 , 60 ]; (iii) introduction of the dienehydrazide groups can obtain potent insecticidal compounds against third-instar larval of C. pipiens [ 65 ]. The introduction of different substituted amides is beneficial for anticancer activity and can obtain a potential inhibitor against CYP2J2 [ 34 , 67 ].…”

“…LC 50 (mg/mL) 1 14.20 [29] 23e 0.16 [29] 23f 0.12 [29] 23u 0.18 [29] 23v 0.16 [29] 25f 0.14 [28] 25l 0.16 [28] 25u 0.19 [28] 25v 0.13 [28] spirodiclofen a 0.12 [29] a Spirodiclofen: a commercial acaricide. As illustrated in Scheme 5, Luo et al synthesized four piperine derivates 35 (4R,5R), 36 (4S,5S), 37 (4S,5R), and 38 (4R,5S), which were established by NMR, optical rotation, and CD spectra [62].…”

“…Recently, our studies synthesized two novel series of ester and oxime ester piperine-type derivatives, some compounds displayed more than 100 times the acaricidal activity of piperine against Tetranychus cinnabarinus (Bois.). Moreover, the scanning electron microscope (SEM) demonstrated that their potential acaricidal activities may be related to the destruction of the construction of the cuticle layer crest of T. cinnabarinus [ 29 , 30 ]. Wang et al found that the ester derivative prepared from piperine exhibited particularly significant broad-spectrum fungicidal activity against Rhizoctonia solani Kühn, Fusarium graminearum Schwabe, Alternaria tenuis Nees, Gloeosporium theae-sinensis I. Miyake, Phytophthora capsica Leonian, and Phomopsis adianticola [ 31 ].…”

A review on oxime functionality: an ordinary functional group with significant impacts in supramolecular chemistry

“…49 Other oxime ester compounds like Matrine ( Oxm-32 ), Fraxinellone ( Oxm-33 ) and Osthole ( Oxm-34 ) are well known for their strong pesticidal properties. 51 In some cases ‘piperine and piperine analogs’ with oxime ester functional group have showed significant pesticidal properties. 51 Oxime-ester derivatives; Oxm-35 (LC 50 = 0.14 mg mL −1 ) and Oxm-36 (LC 50 = 0.13 mg mL −1 ) showed outstanding acaricidal activity against T. cinnabarinus , and it is comparable to the commercial acaricidal agent spirodiclofen.…”