Structure-Repellence Studies on Synthesized Stereoisomers of Menthane-Diol and Analogues against the Rhipicephalus appendiculatus
Muthengi, Alex Mugwiria
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Tick-borne infections of livestock are wide-spread in Africa and present a great constraint to livestock development, particularly in the improvement of local breeds. This problem is compounded by the high susceptibility of foreign breeds of livestock being used to improve livestock productivity in many African countries. Brown Ear tick, Rhipicephalus appendiculatus, is the most economically important of the 40-70 African tick species. This is due to the fact that it is a highly efficient vector of Theileria parva, that causes East Coast Fever (ECF), the tick also causes cutaneous effects such as focal dermal necrosis and irritation, such it‟s the pathogen of the most important and complex tick–borne disease, (ECF). A commonly used commercial arthropod repellent N,N-diethyl-3-methylbenzamide (DEET) is still considered the best available product for repelling arthropods. However, this repellent is harmful to human beings and it has been found to cause considerable environmental pollution. In search for effective alternatives to DEET against different hematophagous arthropods, there has been renewed interest in repellents of botanical origin. A monoterpene of relatively low volatility, p-menthane-3,8-diol, obtained from lemon eucalyptus leaves (Eucalyptus citriodora) has shown potent repellence against mosquitoes. This study sought to undertake structure-activity studies of synthesized p-menthane-3,8-diol stereoisomers and analogues against the Brown ear tick in order to identify structural features associated with high repellency. The essential oil of lemon eucalyptus was extracted by hydrodistillation. Commercial standards of (+) and (−)-isopulegol were hydrated at C-8 using the oxy-mercuration/demercuration procedure to obtain (+) and (–)-trans-p-menthane-3,8-diol respectively. (±)-Cis-p-menthane-3,8-diol stereoisomers were prepared from (±)-citronellal via the Zimmermann and English procedure that involved acid catalyzed cyclization of (±)-citronellal. GC-MS was used to identify the constituents of E. citriodora oil and the structure of the synthesized p-menthane-3,8-diol (PMD) stereoisomers, LC-MS was used to analyze the aqueous fraction. The E. citriodora oil, menthane diol stereoisomers, its analogues and DEET were screened for their repellent activity against R. appendiculatus, through subjecting them to a dual choice tick climbing bioassay. The data obtained was analyzed using (SAS® Institute, 2002-2003, version 9.0) and R-statistical package. Menthane diols were potently repellent (RD75 (1.21– 2.04) ×10-3 mg)) against R. appendiculatus and comparable to that of DEET, 1.43×10-3 mg. Racemates of cis, (RD75 1.42×10-3 mg) and trans 1.42×10-3 mg were as repellent as (+) and (−)-trans diols, (2.03– 2.04) ×10-3 mg. Thus, repellency was neither stereospecific nor stereoselective. PMD analogues of the diol (L-menthol, 1-α-terpineol) showed much lower repellency, RD75, 1734.12 mg and 6960.34 mg against R. appendiculatus compared to p-menthane-3,8-diol stereoisomers. E. citriodora oil had much lower repellency than PMD stereoisomers, but significantly higher repellency than L-menthol and 1-α-terpineol. The yield of E. citriodora oil was 1.84% and the major constituents in E. citriodora oil were citronellal (32.03%), citronellol 19.41%), cineole (9.87%) and isopulegol (5.97%). The aqueous fraction of the hydro-distillate was least repellent to the Brown ear tick and it was found to contain aromadendrene oxide, linalool, citronellic acid and ursolic acid, which have been shown to be weakly repellent to arthropods. Therefore, the structural features required for repellency against R. appendiculatus, according to this study is a saturated menthane skeleton with two hydroxyl functions at C-3 and C-8. The findings of this study lay down the groundwork for search for new user-approved, efficacious tick repellents.