Natural and Semi-Synthetic Compounds with Biocidal Activity Against Arthropods of Public Health Importance
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AN ABSTRACT OF THE DISSERTATION OF Mohammad A. Khasawneh for the degree of Doctor of PhilosoDhy in Chemistry presented on December 5, 2003. Title: Natural and Semi-Synthetic Compounds With Biocidal Activity Against Arthropods Of Public Health Importance. Abstract approved:Redacted for privacy JosephfJ Karchesy This study identified new compounds with pest control activities. The two sources of candidates that were followed here were the main heartwood extract of Alaska Yellow Cedar (AYC) constituents and several semi-synthetic counterparts. Five compounds were isolated and identified for the first time in AYC heartwood in this research: two monoterpenes, two sesquiterpenes, and one lignan. The two monoterpenes were (1 S)-2-oxo-3-p-menthenol (41) and (4R)-4- hydroxy-4-isopropyl-cyclohex-l-enecarboxylic acid (63). The two sesquiterpenes were (5 S,7R, 1 OR, 11 R)-eudesm-4(l 4)-ene- 11,1 2-diol (46) and (4R,5S,7R)- 1(10)- eremohpilen-1 1,12-diol (59). The lignan was (1R,2S,5R,6S)-2,6-bis-(3,5- dimethoxy-4-hydroxyphenyl)-3 ,7-dioxabicyclo- [3.3.01 Qctafle, (67). Structures for these compounds were confirmedon the basis of spectroscopic techniques such as 1- and 2-D NMR, high resolution MS and JR. The pest control activity studies of 15 compounds isolatedor semi- synthesized from AYC heartwood were conducted at the Centers for Disease Control and Prevention (CDC). Two types of studieswere conducted - short-term (24h) and residual (over 1-4 weeks) activity for application against threetypes of pests related to human health- nymphal I. scapularis ticks, adult X cheopis fleas and adult Ae. eagypti mosquitoes. The 24 h studies revealed that nootkatone, valencene-13-aldehyde and valencene- I 3-ol were the most active among the studied compounds against the three pests. They exhibited highly improved pest control activities compared to valencene. This suggests that oxidation on both positions C-2 and C- 13 of the eremophilane ring structure has an important effect on the activity. For compounds where the conformation of the eremophilane bicyclic ring has been altered, the activity seemed to diminish greatly. The above mentioned three compounds can be good candidates as pest control lead compounds. The residual studies revealed that the most active compounds exhibited activity profiles that generally decreased with time. Although the long-term safety of these compounds has yet to be evaluated, the natural origin and the long history of use of these compounds suggest that they can be promising candidates. This study revealed that the three most promising compounds in the 24 h study exhibited reasonably promising behavior, which makes themeven stronger as pest control candidates. ©Copyright by Mohammad Khasawneh December 5, 2003. All Rights Reserved Natural and Semi-Synthetic Compounds With Biocidal Activity Against Arthropods Of Public Health Importance by Mohammad A. Khasawneh A DISSERTATION Submitted to Oregon State University in partial fulfillment of the requirements of the degree of Doctor of Philosophy Presented December 5, 2003 Commencement June 2004 Doctor of Philosophy dissertation of Mohammad A. Khasawneh presented on December 5, 2003. APPROVED: Redacted for privacy Major Prof&ssor, representing Chemistry Redacted for privacy Chair of the Department of Chemistry Redacted for privacy Dean oft e Graduate School I understand that my dissertation will become part of the permanent collection of Oregon State University libraries. My signature below authorizes release of my dissertation to any reader upon request. Redacted for privacy Mohammad A. Khasawneh, Author ACKNOWLEDGEMENTS The author would like to express sincere appreciation to Prof. Joe J. Karchesy for his help, guidance and support during the long process of research design, experimental performance and data analysis. His help and advice during writing this dissertation is extremely important. His financial support is also valuably acknowledged. I would like also to thank my family back home for their patience, support, guidance and prayers through the last six years of my life. The help and support of my wife (Marwah), daughter (Ayah) and son (Faisal) is invaluable. The contribution of Dr. Javier Peralta-Cruz in running some synthesis experiments and NMR data collection is greatly acknowledged. His help and discussions in data interpretation were extremely useful. The discussions with Prof. Ahmed Abmed regarding NMR data interpretation was extremely useful. The contribution of the CDC in the biological evaluation of the compounds is highly acknowledged. Yeping Xioung is acknowledged for starting the phytochemical study of AYC heartwood extract. Rodger Kohnert is acknowledged for his help in the use of the NMR facility. I would also thank colleagues and friends in the Chemistry department for their help. Specifically, I want to mention Dr. Chris Pastorek, Dr. John Loeser, Emile Firpo, Joey Carson and Carolyn Brumely. Finally, I would like to thank friends in Corvallis for their support during difficult times- Awad Gargoury, Salirn Khasawinah, Mounir Louhaichi, and Lo'ai Tawalbeh. TABLE OF CONTENTS 1. Introduction.................................................................. 2 1.1 Terpenes and terpenoids.................................2 1.2 The Alaska Yellow Cedar (AYC) Tree................6 1.3 Arthropods and Human Health.........................10 1.4 Historical use of plants as pest control agents........14 1.5 Examples of plant-derived commercial pest control agents and lead compounds............................15 1.5.1 Pyrethrins....................................... 16 1.5.2Azadirachtins................................. 17 1.5.3 Quassin....................................... 17 1.5.4Examples of natural-based synthetic pest control Agents................................................... 18 1.5.5Non-Commercial promising lead compounds..................................... 18 1.6 Preliminary research....................................21 1.7 Goals of this research....................................21 2. Literature Review.........................................................23 3. Experimental Section.................................................... 33 3.1 Materials and General Methods........................33 TABLE OF CONTENT (CONTINUED) 3.1.1Materials..........................................33 3.1.2General Methods.................................34 3.1.2.1 NMR experiments.......................34 3.1.2.2 Optical rotation measurements......35 3.1.2.3 JR measurements........................36 3.1.2.4 Thin Layer Chromatography (TLC) 36 3.1.2.5 Column Chromatography............37 3.1.2.6 Gas Chromatography..................38 3.2 Plant Materials..........................................39 3.3 Extractions and Isolations..............................39 3.3.1 Steam Distillation..............................39 3.3.2Solvent Extraction..............................40 3.3.3Fractionation of the extract constituents....40 3.4 List of Isolated Compounds with data...............42 3.5 Stereochemistry of nootkatol (42) and 13-hydroxy- valencene (43).......................................... 47 3.6 Syntheses................................................ 48 3.6.1 Synthesis of Nootkatol-(R)-a-Methoxy-a- (trifluoromethyl)phenyl acetate........................48 3.6.2Synthesis of Nootkatol-(S)-a-Methoxy- a-(trifluoro-methyl)phenyl acetate..........48 3.6.3Synthesis of unknown 2 monoacetate......49 3.6.4Synthesis of unknown-3-monoacetate......49 3.6.5Synthesis of Valencene- 1 3-aldehyde.........50 3.6.6Synthesis of valencene-13-ol..................50 3.6.7Synthesis of nootkatone-11, 12-epoxide.....51 3.6.8Synthesis of Nootkatone-1, lO-epoxide......52 3.6.9Synthesis of nootkatone-1,10-11,12- diepoxide..........................................53 3.6.10Synthesis of nootkatin acetate............... 53 3.6.11Synthesis of nootkatin methyl ether............54 TABLE OF CONTENT (CONTINUED) 3.7 List of synthesized derivatives with data 55 3.8 Bioassays............................................. 59 3.8.1 Tick Colonies................................. 60 3.8.2Flea Colonies................................. 60 3.8.3Mosquito Colonies........................... 61 3.9 Bioassay methods.......................................61 3.9.1Tick and Flea Bioassays.......................61 3.9.2Mosquito Bioassay..............................63 3.9.3Residual Activity Experiments...............63 4. Results and Discussion...................................................65 4.1 Structures of newly isolated compounds from AYC Heartwood......................................................65 4.1.1 Unknown 1: (1S)-2-Oxo-3-p-menthenol- (44) 65 4.1.2Unknown 2: (SS, 7R, bR, 11R)-Eudesm- 4(14)-ene-1 1,12-diol, 49...........................74 4.1.3Unknown 3: (4R, 5S, 7R, 11?)-1(10)- Eremohpilen-1 1,12-diol, 62..................... 88 4.1.4Unknown 4: (4R)-4-Hydroxy-4-isopropyl- cyclohex- 1 -enecarboxylic acid, 64............ 97 4.1.5Unknown 5: (1R, 2S, SR. 6S)-2, 6-bis(3, 5- dimethoxy -4-hydroxyphenyl)-3 ,7-dioxabicyclo- [3.3 .Ojoctane,(+)-Syringaresinol (68).......... 105 4.2Settlement of the stereochemical questions about nootkatol and valencene-13-ol.................. 118 4.2.1Nootkatol ((2S, 4R, 5S, 7R)- Eremophil-1- (10), 11 -diene-2-ol), 42................... 118 4.2.2Valencene- 13-ol, (Eremophil- 1(1 0)-, 1 l-dien-13-ol), 43................................. 124 TABLE OF CONTENT (CONTINUED) Semi-synthetic compounds........................... 125 4.3.1Nootkatone-1, 10-epoxide (92)...............126 4.3.2Nootkatone-1