OF PLANT N-ALKYLAMIDES 1.1. Structure 1.2. Occurrence 1.3. Objective 2. Database 3. Clustering 4. Conclusions CHEMICAL-FUNCTIONAL SPACE EXPLORATION OF PLANT N-ALKYLAMIDES Jente Boonen1, Vikas Sharma2, Vinot Dixit2 and Bart De Spiegeleer1* 1 Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium 2 Department of Pharmaceutical Sciences, Dr. H.S. Gour University, Sagar 470003 M.P. India. *Corresponding author: Tel.: +32 9 264 8100; Fax: +32 9 264 8193, E-mail: Bart.DeSpiegeleer@UGent.be 2011-240b

N-Alkylamides 1.1. Structure 1.2. Occurrence 1.3. Objective 2. Database 3. Clustering 4. Conclusions R1= Aliphatic, often unsaturated units, w/wo substutients (N, O, S, cyclic,…) or in cyclic system with R2. R2= Aliphatic, often isobutylamide, methylbutylamide, phenylethylamide, tyramide, piperidide or pyrrolidide derivative, w/wo substituents (N, O, S, cyclic,…) or in cyclic system with R1. R3= Mostly H, Me, MeO, OH function. New group of potential drugs related to lipoid peptides (anti-inflammatory, immunostimulant, anti-hepatotoxic, anti-oxidant, tingling, CB2 endocannabinomimetic, anti-microbial,…) May 2011

Now: 9 different plant families N-Alkylamides 1.1. Structure 1.2. Occurrence 1.3. Objective 2. Database 3. Clustering 4. Conclusions Ceramides Ergopeptides R= aliphatic chain May 2011

No structured overview of plant N-alkylamides ? N-Alkylamides 1.1. Structure 1.2. Occurrence 1.3. Objective 2. Database 3. Clustering 4. Conclusions Plant species N-alkylamide Functionality ? ? Interdisciplinary No structured overview of plant N-alkylamides DATABASE CHEMICAL CLUSTERING May 2011

Relational database, now containing ± 300 plant N-alkylamides CC(C)CNC(=O)\C=C\CC/C=C\C=C\C C14H23NO deca-2E,6Z,8E-trienoic acid isobutylamide (2E,4E,8E)-N-butan-2-yldeca-2,4,8-trienamide spilanthol or affinin Asteraceae Helianthea Spilanthes acmella Anti-oxidant EC50=1.38 µmol N-Alkylamides 2. Database 3. Clustering 4. Conclusions May 2011

3D structure optimization Calculation and selection of 141 descriptors Constitutional descriptors WHIM descriptors Molecular properties - Data-scaling transformation: zi = (хi – x)/SD Multivariate analysis: Hierarchical cluster analysis (HCA) Principal compontent analysis (PCA) N-Alkylamides 2. Database 3. Clustering 4. Conclusions May 2011

HCA => Dendrogram PCA => PC1_PC2 (4 PCs for >70% Q²) 1. N-Alkylamides 2. Database 3. Clustering 4. Conclusions HCA => Dendrogram PCA => PC1_PC2 (4 PCs for >70% Q²) May 2011

Scoring plot Loading plot N-Alkylamides 2. Database 3. Clustering 4. Conclusions Loading plot

QUALITY ATTRIBUTES FOR CLUSTER: (1) Constitutional N-Alkylamides 2. Database 3. Clustering 4. Conclusions QUALITY ATTRIBUTES FOR CLUSTER: (1) Constitutional AMW => molecular weight nAB, nBnZ, nCIC, nRO6 => aromatic ring structures (2) WHIM P2: shape L2: size E2: accessibility (3) Molecular properties Ui => unsaturation index «228» «220» «193» May 2011

DATABASE => EXPLORATORY MINING Chemical/functional overview of plant N-alkylamides CLUSTERING Chemical similarities => Functionality Toxicity PK e.g. transdermal/transmucosal Justified choice of model compounds N-Alkylamides 2. Database 3. Clustering 4. Conclusions May 2011

Thank you for your attention May 2011