LIFE-EDESIA project: overview and Actions B3, B5. Ferdinando Fiorino Francesco Frecentese

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1 LIFE-EDESIA project: overview and Actions B3, B5 Ferdinando Fiorino Francesco Frecentese Università degli Studi di Napoli Federico II (UniNA) Department of Pharmacy Unit of Medicinal Chemistry

2 Lab Profile Principal Investigators Elisa Perissutti, Ferdinando Fiorino, Giuseppe Caliendo, Vincenzo Santagada Francesco Barbato, Lucia Grumetto Department of Pharmacy Synthesis of the novel chemical entities Determination of the technological features and usability University of Naples Federico II, Italy

derivatives to be used as anti-inflammatory agents, serotoninergic ligands, protease inhibitors as antitumoral and antiviral agents.

3 Lab Profile Working experience Our research group has been always involved in medicinal chemistry field. The research of our group is essentially related to design and synthesis of novel heterocyclic compounds, peptides and peptidemimetic derivatives to be used as anti-inflammatory agents, serotoninergic ligands, protease inhibitors as antitumoral and antiviral agents. From several years our interest has been focused on the application of microwave assisted organic chemistry to the synthesis of pharmacologically active compounds.

4 Workplan The LIFE EDESIA project aims to contribute to improve implementation of the REACH Regulation by providing at least one suitable alternative for bisphenol A/BPA, phthalates and parabens. These objectives will be achieved by the following actions:;.synthesizing the selected substitutive chemicals; Creating prototypes that use the substitutive chemicals, and to assess them for release of chemicals; and Demonstrating the feasibility of the substitution of the EDCs considered in the project in industrial applications.

5 Activities in EDESIA ACTION B.3: Synthesis of the chemicals The synthesis will be performed applying the most modern techniques of organic synthesis, developed with particular attention to the environmental impact. Advanced synthetic technologies, such as microwave reactors specifically designed for organic synthesis and all those technologies that allow to perform reactions both in the presence of solvents, such as ionic liquids, alternative to common volatile organic solvents, and in "solvent free" conditions will be used (" Green chemistry ").

Activities in EDESIA The synthesized molecules will be accurately characterized in order to acquire useful

In particular: Definition of lipophilicity to different ph values of physiological relevance; Determination of

various ph; Characterization of possible decomposition products; Development of analytical methods useful for

6 Activities in EDESIA The synthesized molecules will be accurately characterized in order to acquire useful information to streamline their technological characteristics of usability and interaction with living matter. In particular: Definition of lipophilicity to different ph values of physiological relevance; Determination of affinity values for membrane phospholipids and for the serum-proteins; Profiles of solubility in water at various ph; Characterization of possible decomposition products; Development of analytical methods useful for the determination of trace products in biological matrices. This Action will start at month 14 and finish at month 19

7 Activities in EDESIA Task B.5: Prototyping and testing for industrial purposes in 3 application domains Preservatives are widely used, beside in food industry, in both cosmetic and pharmaceutical fields. The use is mainly requested for products containing water to control microbiological growth. It is important to underline that even products based on lipophilic matrices often need the addiction of preservatives since they can include more or less relevant percentages of water. This means that preservatives must be added in a large majority of cosmetic and pharmaceutical preparations, e.g. both liquid and semisolid (lotions and creams, respectively) water in oil or oil in water emulsions, hydrophilic ointments, and even water-absorbing lipophilic ointments.

Activities in EDESIA More relevant for public health is the addiction of preservatives in orally dosage forms such as syrups, often intended for children medication.

8 Activities in EDESIA More relevant for public health is the addiction of preservatives in orally dosage forms such as syrups, often intended for children medication. To date, parabens, the most widely used preservatives, can be replaced (in some cases) by other preservatives, but these compounds show more restricted microbiological properties and application suitability. Better application profiles may be achieved by the new paraben-like compounds synthesized in the present project. Suitability in both cosmetic and pharmaceutical fields will be tested by their inclusion in cosmetic and pharmaceutical preparations, characterized by known composition and possibly already marketed. Their antimicrobial efficacy in these different matrices will be also evaluated as time function. This action will start at month 28 and finish at month 33.

9 Tools Medicinal Chemistry can be a useful tool to get an answer to the first end-point

10 CHEMICAL STRUCTURES OF SOME PHTALATE AND PARABEN DERIVATIVES n-butyl benzyl phthalate (BBP) Dibutyl phthalate (DBP) Propylparaben bis(2-ethylhexyl) phthalate (DEHP) Diisopropyl phthalate (DIP) Butylparaben

11 Research infrastructure Microwave oven specifically designed for Organic Synthesis Microwave oven specifically designed for Combichem Preparative and analytical HPLC LCQ ion trap mass spectrometer API 2000 triple quadrupole mass spectrometer NMR spectrometer 400, 500 and 700 Mhz

12 Microwave heating Advantages The identification of a lead compound starting from a larger compound library is easier. Why is it so popular among Medicinal Chemists? Fast heating allows higher number of componds Use of combinatorial O S chemistry H 3 C H 2 C O O C generation N H approches combined enhances library Higher yields obtained Greener procedures allowed N O 2 Just One winning compound (Drug Candidate) SM-15811: Compound IC Libraries nm

Green Chemistry is the utilization of a set of principles that reduce or eliminate the use or generation of hazardous substances in chemistry.

In this contest, water as solvent is a good option because of its abundant, non-toxic, non-corrosive, and nonflammable nature.

13 Green Chemistry is the utilization of a set of principles that reduce or eliminate the use or generation of hazardous substances in chemistry. Its basic principle is to conduct chemical reactions simultaneously, protecting the environment, through the use of chemical processes deemed suitable to avoid pollution. In this contest, water as solvent is a good option because of its abundant, non-toxic, non-corrosive, and nonflammable nature. Although microwave assisted reactions in conventional solvents have developed rapidly, the center of attention has recently shifted to environmentally benign processes. The association with microwaves allows to overcame problems related to water traditional chemistry such as insolubility of most of organic reactants or difficulty in the product isolation from aqueous reaction mixture. In later years various examples of reaction accelerations, selectivity, and higher yields have been reported using water as solvent or in some cases without the use of any solvent (solvent free reactions).

THE ROLE OF CHEMICAL SYNTHESIS IN SUPPORT OF THE SUBSTITUTION PRINCIPLE Ferdinando Fiorino Elisa Perissutti

Unit of Medicinal Chemistry LIFE-EDESIA workshop Milan, Dicember 10 th 2014 THE ROLE OF CHEMICAL SYNTHESIS IN SUPPORT OF THE SUBSTITUTION PRINCIPLE Ferdinando Fiorino Elisa Perissutti Università degli