Institute of Chemical Scienses Almaty SMART GREEN APPROACHES IN SYNTHETIC DESIGN OF BIOACTIVE POLYFUNCTIONAL AZACYCLIC SYSTEMS Institute of Chemical Scienses Almaty, Kazakhstan Yu Valentina K. Mae, 24,, 2016, Almaty

Introduction There is… possible biologically active substances possible drugs 10 7 known compounds 10 6 commercially available compounds 10 6 compounds in the databases of Companies 10 4 compounds in drugs databases 10 3 commercial drugs 10 2 commercially beneficial drugs Weininger Mae, 24,, 2016, Almaty

Drug Design I. Search and construction of lead-compounds; II. Optimization of lead-compound; III. Development of the drug Introduction Mae, 24,, 2016, Almaty

Optimization of the lead-structure is in elaboration of the synthetic modifications of its structure to: –increase its activity; –reduce its toxicity; –improve the selectivity of action; –prepare molecule with “novel” activity Introduction Mae, 24,, 2016, Almaty

Overview, approach, objectives, milestones, and measurements of success Mae, 24,, 2016, Almaty

Anesthetic and anti-Arrhythmic Overview, approach, objectives, milestones, and measurements of success Mae, 24,, 2016, Almaty

Spasmolytic activity and acute toxicity Compound Reduction of intestine after introduction of the compound, mm (M ± m) Reduction of intestines on the background of compound after introduction of acetylcholine mm(M±m) Reduction of intestines on the background of compound after introduction of 10% solution of calcium chloride, mm (M±m) LD 50, mg/kg NA-348 NA-349 NA-350 NA-351 NA-352 Drotaverine Eufillin Acetylcholine Calcium Chloride ± ± ± ± ± ± ± ± ± ±0.0 2, ± ± ± ±14.40 более ± ±17.21 A. Zh. Kabdraisova,M. F. Faskhutdinov, V. K. Yu, K. D. Praliev, E. E. Fomicheva,S. N. Shin, and K. D. Berlin Chemistry of Natural Compounds, Vol. 43, No. 4, 2007 Overview, approach, objectives, milestones, and measurements of success Mae, 24,, 2016, Almaty

The main Research idea is in the synthetic studies "docking" to the structure of a fragment of the above natural compounds, and N-alkoxyalkylpiperidine. Application of the methods of both classical organic synthesis and green chemistry approach provides novel systems with the potential pharmacological activity. Research Description Mae, 24,, 2016, Almaty

4- Ethynylpiperidines - "Privileged Structures“; Molecular design of the 4-Ethynylpiperidine is an effective "tool (instrument)" for the creation of valuable drugs that have a wide range of pharmacological effects; The strategy of target search of lead-compounds - «through put» screening, the use of already known drugs as the lead-compound and its rational design; The most perspective lead-compounds - piperidine derivatives with ether bond in the substituent at the nitrogen atom, and available natural compounds. Research Description Mae, 24,, 2016, Almaty

 Modification of natural compounds - an introduction to the structure of alkaloids and synthetic analogs of groups that enhance the therapeutic effect or change the biological activity.  Microwave radiation - an alternative source of power for many organic reactions performed by heating and accelerating many times compared with traditional conditions of synthesis.  Reducing the duration of organic synthesis and expansion of its range of reactions using microwaves - the key to reducing the production time of new high-effective biologically active substances. Research Description Mae, 24,, 2016, Almaty

N- alkoxyalkylpiperidine-containing objects of Research Research Description Mae, 24,, 2016, Almaty

The replacement of the benzoyl to the acetyl or propionyl group in the acyl fragment of the molecule of Kazcain does not lead to loss of the anesthetic properties. The level of effect and duration of the actions of acetates and propionates <<< benzoate Research Description Mae, 24,, 2016, Almaty

1-(2-ethoxyethyl)-4-ethynypiperidine-containing acid, its nitrile and amidoxime inhibit the growth of gram-positive (Staphylococcus) and gram- negative (E. coli and Salmonella) microorganism, i.e. exhibit a pronounced antibacterial activity. Acid causes expressed analgesia in experiments on rats. Research Description Mae, 24,, 2016, Almaty

Phenoxyalkyl Ethers of 1-(2-Ethoxyethyl)-4-ethynyl-4-hydroxypiperidine have a wide spectrum of pharmacological action. On the model of «Tail-flick» they have a high analgisic effect. Duration of analgesia drugs ranges from 183 to 221 minutes, whereas Tramal causes analgesia during 75 min. Furthermore, Tramal does not cause a deep analgesia unlike the new derivatives. Furthermore, Phenoxyalkyl ethers inhibit the growth of disease-causing bacteria and remove the spasm caused by histamine and calcium chloride. Research Description Mae, 24,, 2016, Almaty

Propargylamine based on 1-ethoxyethyl-4ethynyl--4-hydroxypiperidine showed clearly expressed analgesic activity. In duration of analgesia the drugs 2-3 times exceed the effect of the reference drug Tramal, the duration of deep analgesia of new derivatives is from 130 to 240 minutes. Some preparations inhibit the growth of disease-causing bacteria. Synthesized propargyl derivatives as complexes with β-cyclodextrin are low toxicity compounds, beacuse LD50 of the most preparations are in the range of mg / kg. Research Description Mae, 24,, 2016, Almaty

Research Description Mae, 24,, 2016, Almaty

Conclusion As a result of the project implementation will: 1. synthesize new potentially active systems with obligatory fragments of N-alkoxyalkylpiperidine 2. evaluate their biological activity and toxicity; 3. issue recommendations to carry out the study of specific activity and chronic toxicity (pre-clinic) Mae, 24,, 2016, Almaty

MANY THANKS