Scientific project

«Screening of the bioactive substances from the Central Asian flora to reveal antituberculosis, antineoplastic,

neurotropic, antiviral and antiparasitic agents»

The Institute of the Chemistry of Plant Substances named after academician S.Yu.Yunusov, Academy of Sciences,

Republic of Uzbekistan

What’s the problem?In accordance with WHO calculations, infectious, oncologic, viral infections, neurological disorders are included in the ten of actual diseases affected to the Earth population.

Plant substances shown high biological activity in treatment of tuberculosis, cancer, malaria, helminthiases, Alhzaimer disease etc. But the range of known therapeutic remedies is not so wide, while the medicine needs new drugs due to development of pathogenes’ resistance to known drugs, side effects of known drugs, as well as mutations and appearance of new properties in strains of pathogenes.

Uzbek flora includes more 4500 species of wild growing plants, 1150 of them are used in medicine. Officially more 100 plant species are included in Uzbek Pharmacopeia. Antituberculosis, antineoplastic, neurotropic, antiviral, ahtiparasitic properties of substances contain in these plants are not investigated systematically.

Aim and objectives

• Aim of the project: screening of the biologically active substances (alkaloids, terpenoids, phenolic substances and their derivatives), determination, pharmacological and molecular investigation of perspective leading substances for drug development.

Objectives: • identification and comprehensive investigation of perspective plant

substances with antituberculosis, antineoplastic, neurotropic, antiparasitic, antiviral activity,

• investigation of their pharmacology and safety, mechanisms of action,

• creation of theoretical base for virtual screening of the investigated classes of compounds, modeling of their interaction to cellular targets,

• preparation of qualified staff.

Planning activities under the project:

• Signing agreements on scientific collaboration and confidentity between ICPS and scientific centers of EU, USA and China intend to take part in the project. Formation and filing to international scientific funds of four sub-projects aimed to investigation of separate kinds of biological activity under this project is foreseen;

• Preparing of the library of substances isolated from the Central Asian flora (alkaloids, terpenoids, phenolic substances and their derivatives);

• Screening and investigation of biological activity of these substances to reveal the leading substances with antituberculosis, antineoplastic, neurotropic, antiparasitic/antiprotozoal (malaria, leishmaniasis, helminthiases etc.), antiviral (hepatitis B and C, influenza and haemorrhagic fevers etc.) activity;

• Modeling of interaction of the targeted substances to their molecular targets, creation of systems for virtual screening of the investigated classes of substances and kinds of biological activity;

• Investigation of pharmacology and safety of studied substances;• Improvement of qualification of young scientists.

Sub-projects assumed inside this project

I. Screening, pharmacological and molecular investigation of neurotropic (antagonistic to neurotoxins and nootropic) activity of diterpene alkaloids of Aconitum and Delphinium plants

II. Screening, pharmacological and molecular investigation of antituberculosis and antiparasitic/antiprotozoal activity of plant substances isolated from the Central Asian flora and their derivatives

III. Screening, pharmacological and molecular investigation of antiviral activity of plant substances isolated from the Central Asian flora and their derivatives

IV. Screening, pharmacological and molecular investigation of antineoplastic activity of plant substances isolated from the Central Asian flora and their derivatives

We assumed to use modern approaches to investigation of biologically active substances: systematic and total screening, computer modeling of interaction of studied substances and pharmacological targets, structure-activity relationship (SAR), instrumental and biophysical methods of investigations etc.

Scientific experience and investigation ability of the

Institute of the Chemistry of Plant Substances – applicant

institution

The Institute of the Chemistry of Plant Substances named after academician S.Yu.Yunusov, Academy of Sciences, Republic of Uzbekistan (ICPS) is the scientific-investigation institution realizes complex investigations in medicinal and agricultural preparations development, including botanical, chemical, pharmacological, toxicological study, computer modeling of structures and properties of natural substances, and manufacture of drug substances and preparations for agriculture

2

How did drugs develop in ICPS

Complex - «conveyor» system of drugs creation.

Botanical investigation

Chemical investigations

Biological activity screening

Pharmacological and toxicological

investigations

Working out technologies for drug substances and drug forms manufacture

Clinical

trials

Introduction into practice

Institute Institute’s structure and staff:• 11 chemical laboratories• Organic synthesis department• Pharmacology and toxicology department • Technology department with Pilot manufacturing• Marketing department• Agency for certification of fertilizers, pesticides

and plants protection means and Testing center • “Chemistry of Natural Compounds” Journal

Publishers• Mini printing office • Library

Total staff - 350 employers Scientists - 160

DSci – 23, PhD - 77

ICPS scientific activity1. Chemistry of natural compounds – isolation, structural

investigation and chemical modification of natural compounds

2. Pharmacology and toxicology of natural compounds - screening for different kinds of biological activity, investigation of action mechanisms of natural and modified substances as a base for new physiologically active substances targeted search, and preclinical investigations of candidate substances

3. Agricultural chemistry - creation of plant protection means – plant growth stimulators, herbicides, fungicides, defoliantes etc.

4. Preparations for veterinary – creation of preparations for animal breeding and poultry

5. Phytopreparations technology – working out new effective technologies, manufacture of drug substances and plant protection means on Pilot manufacturing

Institute of the Chemistry of Plant Substances is one of the world leading centers in phytochemistry.

• More than 1200 alkaloids, 350 glycosides, 500 coumarines, flavonoids, lactones, proanthocyanidines, 50 lipids and 30 polysaccharides have been isolated by scientists of the Institute

• Molecular structures of 625 new alkaloids, 350 new glycosides, 300 coumarines, flavonoids, terpenoids, complex ethers, lactones and proanthocyanidines have been elucidated

ICPS: phytochemical investigations and biological activity screening

Alkaloids

1270 substances, 650 new

antiarrhythmic, anticholinesterase, sedative-tranquilizer, antinociceptive, antiinflammatory, hypotensive, anticonvulsant, antituberculosis, expectorant, psychotropic and other kinds of biological activity

Terpenoids

1000 substances, 430 new

Estrogenic, angioprotective, hypolipidemic, antiinflammatory, cardiotonic, immunostimulative, tonic etc.

Phenolic substances

more 500 substances, 270 new

Bile excreting, bactericidal, spasmolytic, cardiotonic, hypolipidemic, antihypoxive, photosensibilizing, antiinflammatory etc.

ICPS: pharmacological and toxicological investigations of plant substances

Pharmacological properties and molecular mechanisms of 2000 newly isolated plant substances belong to different classes were characterized

New substances with high antiarrhythmic, antiatherosclerotic, cardiotonic, hypotensive, antitumor, psyhotropic, neuroprotective, curariform, hepatoprotective, antiinflammatory, antidiabetic and other types of biological activity were identified.

In cooperation with chemists and technologists the drugs based on phytoecdisteroids: ecdisten, ajustan, exumide as tonic, adaptogenic, stress-protective remedies; allapinine and aclesine as antiarrhythmics; dezoxypeganine, galantamine as anticholinesterase remedies; tefestrol and ferulen as estrogenic remedies and other drugs were introduced in practice.

The relationship between chemical structure and some kinds of biological activity were founded. Pharmacophores and toxophores responsible to biological activity and toxicity were determined.

ICPS: instrumental methods and computational simulation

104 diterpene alkaloids isolated from Aconitum and Delphinium were investigated by molecular computational simulation

and QSAR

The most significant parameters (descriptors) responsible for toxicity of curariform, antiarrhythmic and other alkaloids from this range were founded

Algorithm for selection of informative descriptors significant for displaying of biological effects, and construction of prognostic “structure-activity” model was proposed

High predictive probabilistic mathematical models coupling the values of physical-chemical and quantum-chemical indicative descriptors and data in anti-arrhythmic activity and toxicity were obtained for series from 65 diterpene alkaloids

It was shown, that diterpene alkaloids conform to the Rules of Lipinski.

In accordance with Rule of Lipinski these substances were divided to high-perspective and low-perspective groups of potential drugs.

Technological achievements

Development of new profitable technologies of natural substances

Alkaloids Terpenoids Phenolic substances

On the base of the dependence of alkaloids distribu-tion in hetero-phase systems from Rf и pH1/2 new technologies for obtaining of more 35 individual physiologically active alkaloids were worked out.

The original methods for purification of isoprenoids sum by sorption from extract the ballast substances on ion-exchange resins and isolation by liquid-liquid extraction. Technologies more 15 preparations based on isoprenoids and their glycosides were worked out in accordance with this method.

Technologies for manufacture of 10 preparations on the base of phenolic substances were worked out after investigation of sorption and desorption of phenolic substances on ion-exchange and polyamide resins.

Medicines introduced in practice

Preparation Prescription

Allapinin® Antiarrhythmic

Galantamine ® Choline esterase inhibitor

Desoxypeganine ® Choline esterase inhibitor

Ecdisten ® Actoprotector and adaptogenic

Тefestrol ® Estrogenic

Оlygvon Antiatherosclerotic

Cytizine Analeptic

Cucumazime ® Enzymatic (for surgery, ophthalmology, “diabetic foot” treatment etc.)

and others

How scientific work under the project should be organized

ICPS:

Isolation of individual plant substances, identification of structure, chemical transformations

Pharmacology and toxicology on animal models using pharmacological analyzers

Study of the interaction of the target molecules to cellular targets using computational methods

Molecular docking

Foreign collaborators:

HTS, total screening

Pharmacology in vitro

Study of the interaction of the target molecules to cellular targets using molecular biology and electrophysiology methods

Study of the targeted pharmacological activity of leading substances on genetic animal models

Expected results

• Antituberculosis, antineoplastic, neurotropic, antiparasitic, antiviral leading substances for drug development will be recommended after screening, pharmacological and molecular investigation.

• Theoretical base for development of virtual screening systems for such classes of substances and modeling of their interaction to cellular targets will be founded.

• Obtained results will be claimed in patents and publications in scientific journals, as well as they will be used for further chemical transformation of leading substances in order to increasing their biological activity or optimization of their properties.

• Perspective young scientists can improve their qualification in leading scientific centers.

• The necessary equipment will be purchased.

Scientific funds for possible supportingof the project

• «Horizon 2020» – 8th Framework Program of European Union

• CRDF – US Civilian and Research Development Foundation

• NSF – US National Scientific Foundation• US National Health Institute

• Other international scientific funds open for Uzbekistan

Contact person:

Firuza M.Tursunkhodjaeva, PhD• position: senior scientist in the Pharmacology

and Toxicology Department, Institute of the Chemistry of Plant Substances, Uzbek Academy of Sciences

• phone: +998(71)262-72-85• e-mail: plant_inst@icps.org.uz;

ftm40438@gmail.com

http://uzicps.uz/