Papyracillic acid and its derivatives as biting deterrents against Aedes aegypti(Diptera: Culicidae): structure–activity relationships

Authors: CIMMINO, ALESSIO - The University Of Naples Federico Ii; EVIDENTE, MARCO - The University Of Naples Federico Ii; MASI, MARCO - The University Of Naples Federico Ii; ALI, ABBAS - University Of Mississippi; TABANCA, NURHAYAT - University Of Mississippi; KHAN, IKHLAS - University Of Mississippi; EVIDENTE, ANTONIO - The University Of Naples Federico Ii

Submitted to: Medical Chemistry Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/17/2015
Publication Date: 8/30/2015
Citation: Cimmino, A., Evidente, M., Masi, M., Ali, A., Tabanca, N., Khan, I.A., Evidente, A. 2015. Papyracillic acid and its derivatives as biting deterrents against Aedes aegypti(Diptera: Culicidae): structure–activity relationships. Medical Chemistry Research. 24:3981-3989.

Interpretive Summary: Aedes aegypti L. is the major vector of the arboviruses responsible for dengue fever, one of the most devastating human diseases. Papyracillic acid, the main phytotoxin produced by Ascochyta agropyrina var. nana, was evaluated in a preliminary screening together with other fungal phytotoxins, cyclopaldic acid, seiridin, and sphaeropsidin. These compounds were also tested for the biting deterrent and larvicidal activities against Ae. aegypti. Papyracillic acid showed a strong mosquito biting deterrent activity in screening bioassay. Five already known and six new derivatives were then prepared with the aim to carry out a structure-activity relationship study. In this study, biting-deterrent activities of the fungal phytotoxins cyclopaldic acid (1), papyracillic acid (5), sphaeropsidin A (4), and seiridin (2), as well as larvicidal activities of compounds 1 and 4 were evaluated. A series of derivatives of 1, 2, and 4 were semi-synthesized and assayed for further structure-activity relationship studies. The bioassay results indicate that structural features responsible for the activity of compounds 1, 2, and 4 were the presence of a CHO or CH2OH group at C(4), an unaltered butenolide ring, and the presence of a C¼O or a secondary OH group at C(7). Sphaeropsidin B (4C) was the most active biting deterrent, followed by 2’-Oacetylseiridin (2A) which also showed good larvicidal activity. Compounds 2A and 4C, which can also be prepared in only one step in high yield from 2 and 4, respectively, could be considered as potential natural biting deterrents against Ae. aegypti.

Technical Abstract: Aedes aegypti L. is the major vector of the arboviruses responsible for dengue fever, one of the most devastating human diseases. Papyracillic acid, the main phytotoxin produced by Ascochyta agropyrina var. nana, was evaluated in a preliminary screening together with other fungal phytotoxins, cyclopaldic acid, seiridin and sphaeropsidin A for their biting deterrent and larvicidal activities against Ae. aegypti. Because papyracillic acid previously showed a strong mosquito biting deterrent activity, five already known and six new derivatives were prepared in the current study to carry out a structure-activity relationship. All the compounds showed biting deterrence higher than the solvent control, ethanol. Biting deterrent activity of compounds 8, 9, 10 and 12 with biting deterrent index values of 0.76, 0.86, 0.72 and 0.74 nmol/ cm2 was similar to DEET, which was 25 nmol/cm2. None of these compounds showed any larvicidal activity at the highest testing dose of 100 ppm. The bioassay results indicated that the structural feature responsible for the activity of compound 1 was probably the furanone ring. The presence of the alternative substituted cyclobutene, oxiran or substituted 4H-1,2,3-oxadiazine rings in some derivatives may be responsible for an increase in activity.