Design, synthesis and evaluation of 3-arylidene azetidin-2-ones as potential antifungal agents against Alternaria solani Sorauer.

A new concise and facile method was explored to synthesize a collection of new 3-arylidene azetidin-2-ones, which could be regarded as the derivatives of the hybrid scaffold of bioactive natural cinnamamide and heterocycle azetidi-2-one. The structures of the synthesized compounds were characterized by 1H, 13C NMR, and MS; and their antifungal activity were evaluated against Alternaria solani Sorauer. These antifungal data were subjected to a quantitative structure-activity relationship (QSAR) analysis using Codessa software on the basis of the results from B3LYP/6-31G(d,p) quantum calculations. The best regressive model revealed that potentially more active compounds should have low dipole moments and QC-min (minimal net atomic charge for a C atom), and high QO-max (maximal net atomic charge for an O atom) and QN-min (minimal net atomic charge for an N atom). The most potent compound 7k could lead to intracellular accumulation of reactive oxygen species, dissipation of mitochondrial transmembrane potential, and an autophagy-like cell death process in A. solani Sorauer. Taken together, these results laid the foundation for further design of improved crop-protection agents based on this hybrid scaffold.

[1]  Yan Yin,et al.  Preparation, Characterization and Nematicidal Activity of Lansiumamide B Nano-Capsules , 2012 .

[2]  M. Karelson,et al.  Quantum-Chemical Descriptors in QSAR/QSPR Studies. , 1996, Chemical reviews.

[3]  A. Starkov,et al.  Mitochondrial targets of drug toxicity. , 2000, Annual review of pharmacology and toxicology.

[4]  Lichun Li,et al.  Larvicidal activity of lansiumamide B from the seeds of Clausena lansium against Aedes albopictus (Diptera: Culicidae) , 2012, Parasitology Research.

[5]  Robert S. Balaban,et al.  Mitochondria, Oxidants, and Aging , 2005, Cell.

[6]  D. Bebber,et al.  Crop-destroying fungal and oomycete pathogens challenge food security. , 2015, Fungal genetics and biology : FG & B.

[7]  David J Newman,et al.  Natural products as sources of new drugs over the 30 years from 1981 to 2010. , 2012, Journal of natural products.

[8]  Xiaoyi Wei,et al.  Two New Antifungal Alkaloids Produced by Streptoverticillium morookaense , 2007, The Journal of Antibiotics.

[9]  T. Singh,et al.  Microscopic, Biochemical and Physiological Assessment of the Effect of Methylene Bisthiocyanate on the Sapstain Fungus Ophiostoma floccosum , 2006, European Journal of Plant Pathology.

[10]  Charles L Cantrell,et al.  Natural products as sources for new pesticides. , 2012, Journal of natural products.

[11]  Malcolm E. Davis,et al.  Solid-phase synthesis and SAR of 4-carboxy-2-azetidinone mechanism-based tryptase inhibitors. , 2004, Bioorganic & medicinal chemistry letters.

[12]  A. Mehta,et al.  Synthesis and Antifungal Activity of Azetidinone and Thiazolidinones Derivatives of 2-Amino-6-(2-naphthalenyl)thiazolo[3,2-d]thiadiazole , 2006 .

[13]  D. Hollomon.  Fungicides for Plant Diseases , 2009 .

[14]  D. Selwood,et al.  Two- and Three-dimensional Rings in Drugs , 2014, Chemical biology & drug design.

[15]  Peter Daszak,et al.  Emerging infectious diseases of plants: pathogen pollution, climate change and agrotechnology drivers. , 2004, Trends in ecology & evolution.

[16]  N. Pai,et al.  Synthesis and biological activity of N-substituted-3-chloro-2-azetidinones. , 2007, Molecules.

[17]  Antoon Bronselaer,et al.  Alkamid database: Chemistry, occurrence and functionality of plant N-alkylamides. , 2012, Journal of ethnopharmacology.

[18]  D. Guest,et al.  Fungal and Oomycete Diseases of Tropical Tree Fruit Crops. , 2016, Annual review of phytopathology.

[19]  Y. Fort,et al.  The ‘Baylis - Hillman Reaction’ mechanism and applications revisited , 1992 .

[20]  B. Van Houten,et al.  Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[21]  E. Barriuso,et al.  Prediction of the Fate of Organic Compounds in the Environment From Their Molecular Properties: A Review , 2015, Critical reviews in environmental science and technology.

[22]  R. Buchholz,et al.  α‐Methylidene‐ and α‐Alkylidene‐β‐lactams from Nonproteinogenic Amino Acids , 1991 .

[23]  D. Ivić.  Curative and Eradicative Effects of Fungicides , 2010 .

[24]  D. R. Crocker,et al.  Plant chemistry and bird repellents , 2008 .

[25]  Z. Elazar,et al.  Regulation of autophagy by ROS: physiology and pathology. , 2011, Trends in biochemical sciences.

[26]  M. Itoigawa,et al.  Lansiumamide B and SB-204900 isolated from Clausena lansium inhibit histamine and TNF-α release from RBL-2H3 cells , 2013, Inflammation Research.

[27]  D. Los,et al.  Quantitative structure-activity relationship analysis of perfluoroiso-propyldinitrobenzene derivatives known as photosystem II electron transfer inhibitors. , 2012, Biochimica et biophysica acta.

[28]  D. Cowan,et al.  Cinnamamide, an avian repellent, reduces woodpigeon damage to oilseed rape , 1998 .

[29]  S. Rodríguez-Enríquez,et al.  Selective degradation of mitochondria by mitophagy. , 2007, Archives of biochemistry and biophysics.

[30]  Katie Chan,et al.  Drug-induced mitochondrial toxicity , 2005, Expert opinion on drug metabolism & toxicology.

[31]  J. Brownstein,et al.  Emerging fungal threats to animal, plant and ecosystem health , 2012, Nature.

[32]  Charles L Cantrell,et al.  Natural products in crop protection. , 2009, Bioorganic & medicinal chemistry.

[33]  Paweł Bednarek,et al.  Secondary metabolites in plant innate immunity: conserved function of divergent chemicals. , 2015, The New phytologist.

[34]  Zvulun Elazar,et al.  ROS, mitochondria and the regulation of autophagy. , 2007, Trends in cell biology.

[35]  P. Russell.  The development of commercial disease control , 2006 .

[36]  Erol Eroglu,et al.  A DFT-based quantum theoretic QSAR study of aromatic and heterocyclic sulfonamides as carbonic anhydrase inhibitors against isozyme, CA-II. , 2007, Journal of molecular graphics & modelling.

[37]  Y. Aoyama,et al.  Design, synthesis and pharmacological evaluation of 3-benzylazetidine-2-one-based human chymase inhibitors. , 2001, Bioorganic & medicinal chemistry.

[38]  T. Sparks,et al.  Natural products, their derivatives, mimics and synthetic equivalents: role in agrochemical discovery. , 2017, Pest management science.

[39]  J. Turrens,et al.  Mitochondrial formation of reactive oxygen species , 2003, The Journal of physiology.

[40]  Wilfried Langenaeker,et al.  Atomic charges, dipole moments, and Fukui functions using the Hirshfeld partitioning of the electron density , 2002, J. Comput. Chem..

[41]  F. Rocco,et al.  Evaluation of analgesic and anti-inflammatory activity of novel beta-lactam monocyclic compounds. , 2000, Biological & pharmaceutical bulletin.

[42]  Richard D. Taylor,et al.  Rings in drugs. , 2014, Journal of medicinal chemistry.

[43]  Z. Tu,et al.  Antioxidants and α-glucosidase inhibitors from Ipomoea batatas leaves identified by bioassay-guided approach and structure-activity relationships. , 2016, Food chemistry.

[44]  S. Sollott,et al.  Mitochondrial ROS-induced ROS release: an update and review. , 2006, Biochimica et biophysica acta.

[45]  Thomas C Sparks,et al.  Natural products for pest control: an analysis of their role, value and future. , 2014, Pest management science.

[46]  H. Majima,et al.  Evidence of ROS generation by mitochondria in cells with impaired electron transport chain and mitochondrial DNA damage. , 2007, Mitochondrion.

[47]  S. Gavrilets,et al.  Linking the emergence of fungal plant diseases with ecological speciation. , 2010, Trends in Ecology & Evolution.

[48]  Guobin Zhang,et al.  Antibacterial activity of Lansiumamide B to tobacco bacterial wilt (Ralstonia solanacearum). , 2014, Microbiological research.

[49]  Thomas C Sparks,et al.  Perspectives on the agrochemical industry and agrochemical discovery. , 2017, Pest management science.

[50]  D. Newman,et al.  Natural products as sources of new drugs over the last 25 years. , 2007, Journal of natural products.

[51]  S. Gürtler,et al.  β-Lactam derivatives as potential anti-cancer compounds , 2008 .

[52]  Diogo M. Camacho,et al.  Fungicidal drugs induce a common oxidative-damage cellular death pathway. , 2013, Cell reports.

[53]  Parul D. Mehta,et al.  2-Azetidinone--a new profile of various pharmacological activities. , 2010, European journal of medicinal chemistry.

[54]  S. Duke,et al.  Natural products for pest management , 2006 .