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Eugenia Stingaci - PhD in Chemistry from 1974 was born on December 3, 1939. Dr. Stingaci is expert in the chemistry of biologically active polycyclic compounds. Previously, she has successfully participated as executor in other international projects (MD-Ukraine project Ref. № 10.820.09.01/UA, MD-US projects CRDF/MC2-3007). During the last 5 years, Stingaci E. has published 14 scientific articles and has been author of 2 patented inventions. Languages: Russian, Romanian, English, Germany.



Natalia Sucman - PhD in Chemistry from 2013 was born on November 9, 1983. Junior researcher at the laboratory of Organic Synthesis of Institute of Chemistry, ASM. Over the last years she is specializing in various aspects of organic and medicinal chemistry and currently engaged in projects directed at optimisation of the conditions of enantio- and stereoselective obtaining of different derivatives of spirocycloisatines, at asymmetric induction in carbenoid reaction by means of a chiral organic and inorganic catalysts, at reactions which proceed with high levels of regio- and stereoselectivity, ionic liquids as green alternatives to solvents and the total synthesis of biologically active products by use computer-aided molecular design and structure-activity analysis. Since 2006, Ms. Sucman has published 4 scientific articles, 15 conference abstracts and has been author of 1 patented invention. Ms. Sucman has participated in 3 international projects as executor (MD-Ukraine project Ref. № 10.820.09.01/UA, MD-Germany project Ref. № 09.820.05.08 GF, The Royal Society International Joint Project Ref. № JP090309). In 2008, she was awarded with Scholarship for Excellence by the Government of Moldova; attended the NATO Advanced Study Institute in the field of Green Metathesis Chemistry (Bucharest). In 2009, Ms. Sucman won one-year scholarship of ICSC – World Laboratory (Switzerland) in field of the inhibitors of HIV.

Languages: Russian, Romanian, English.
Marina Zviaghinteva - MS in Chemistry form 1999 was born on August 6, 1973.

Since 2007, the scientific researcher at the laboratory of Organic Synthesis of Institute of Chemistry, ASM. Over the last years she is specializing in various aspects of organic, medicinal and natural compounds chemistry. Since 2006, Ms. Zviaghinteva has published 5 scientific articles, 15 conference abstracts and has been co-author of 1 patented invention. As co-author: Bronze Medal at the International Expo – Euroinvent 2012 (Iasi, EU).



Languages: English, Russian, Romanian.
Vsevolod Pogrebnoi - MS in Chemistry form 2012 was born on July 8, 1987. Since 2010, the Junior researcher at the laboratory of terpenoids chemistry of Institute of Chemistry, ASM. The field of scientific interests of Mr. Pogrebnoi is dedicated to the stereoselective synthesis and study of chiral optically active oxindoles. Pogrebnoi V. has published 1 scientific articles, and 5 conference abstracts.

Languages: English, Romanian, Russian.
Veaceslav Boldescu – PhD in Chemistry was born on January 8, 1983. Since September 2004, a senior lecturer at the Department of Industrial and Ecological Chemistry, State University of Moldova, where gained a lot of experience in managing the didactic and research processes; in development and elaboration of curricula for different disciplines according to the Bologna standards. Since January 2009, as FP7 Energy & Environment NCP in the Republic of Moldova participated in a number of trainings on project management, technology transfer, scientific results marketing, and innovation management. Dr Boldescu participated as executor and project manager in 2 national and 3 international projects (CRDF, USA; Coimbra Group, EU). In 2010, Dr. Boldescu was awarded with the National Youth Award in the field of Science and Technology and won the International Youth Innovational Competition between the CIS states with the individual project in the field of pharmaceutical nanotechnology.

Languages: English, Romanian, Russian

The Institute of Phthisiopneumology "Chiril Draganiuc" is a strategically medical unit for the Republic of Moldova and coordinate the achievement of the National programme of Control and Prophylaxis of tuberculosis. The Institute grants yearly specialized medical assistance to about 30000 patients with tuberculosis and non specifically affections of the breathing apparatus. As part of the Institute of Phthisiopneumology" Chiril Draganiuc" work 10 sections and scientific laboratories; 7 clinical sections with 300 beds, the Anaesthesiology and Rheumatology section and 8 Paraclinic sections and laboratories endowed with modern laboratory and medical equipment. By the Institute of Phthisiopneumology "Chiril Draganiuc" are formed 2 Specialised Scientific Councils, ability with the right to organize the upholding of the doctorate' s thesis: the Specialized Scientific Council DH 54.14.00.26, at the speciality 14.00.26 – Phthisiopneumology, and the Specialized Scientific Council DH 54.14.00.36, at the speciality 14.00.36 – Diagnosis of laboratory, Immunology and allergology. The profile Specialized Seminar on the specialities: 14.00.26 – Phthisiopneumology and 14.00.36 – Laboratorial Diagnostics; Immunology and Allergology. The Phthisiopneumology Society from the RM works as part of the Institute.
At the base of the institute is situated the Department of Pneumophthisiology of the SMFU ''N. Testemitanu''.
Valeriu Crudu - PhD in medicine – 1990, Academy of Sciences “I. Secenov”, Moscow, Russia, was born on February 1, 1957. Chief of National Reference Laboratory of Institute of Phthisiopneumology of Moldova since 1991 up to present time. He has worked as researcher at the Institute of Phthisiopneumology of Moldova since 1990. Dr. Crudu participated as executor and project manager in 3 tuberculosis related projects: Project UCSD : “Rapid Tests for Drug Resistance to Detect Extensively Drug-Resistant Tuberculosis” 2009-present; “Studying the phenomenon of nosocomial transmission of MDR TB by genotypic analysis of DNA diversity of M.tuberculosis strains (FINGERPRINTING METHOD) 01.01.12-31.03.12”; “The studying of antituberculosis activity of new synthesized compounds of tioureide 2-(2–phenylethyl)-benzoic acid” 2010-2012. He is author and co-author of 111 publications and scientific presentations. Area of expertise: tuberculosis microbiology, tuberculosis drug resistance, the study of compounds with biological activity.

Languages: Romanian, Russian, English.

Elena Romancenco was born on January 10, 1974

Mrs Romancenco graduated from the State University of Medicine and Pharmacy “NICOLAE TESTEMITANU” in 1998. Afterwards, she worked at the National Center for Public Health, Chisinau from 2001 to 2007. She has been working at the Institute of Phthisiopneumology of Moldova as main microbiologist from 2011-present. She is author and co-author of 21 publications and scientific presentations.

She has participated in the following projects: USAID project “Prevention of HIV and viral hepatitis B &C in Moldova” as Specialist in Laboratory Diagnostics, Chisinau 2007-2008; UCSD project: “Rapid Tests for Drug Resistance to Detect Extensively Drug-Resistant Tuberculosis” 2009-present; project “Studying the phenomenon of nosocomial transmission of MDR TB by genotypic analysis of DNA diversity of M.tuberculosis strains (FINGERPRINTING METHOD) 01.01.12-31.03.12; and “The studying of antituberculosis activity of new synthesized compounds of tioureide 2-(2–phenylethyl)-benzoic acid” 2010-2012. Since 2006, she has been working as assitant professor at the State University of Medicine and Pharmacy “NICOLAE TESTEMITANU”.Area of expertise: tuberculosis microbiology, tuberculosis drug resistance, the study of compounds with biological activity.

Languages: Romanian – native, Russian – fluently, English – fluently
Ecaterina Stratan was born on March 30, 1986

Mrs. Stratan graduated from the State University of Medicine and Pharmacy “NICOLAE TESTEMITANU” in 2010. She has been working at the Institute of Phthisiopneumology of Moldova as fellow researcher since 2008-present. She has participated in the following projects: “Rapid Tests for Drug Resistance to Detect Extensively Drug-Resistant Tuberculosis” 2009-present; “Studying the phenomenon of nosocomial transmission of MDR TB by genotypic analysis of DNA diversity of M.tuberculosis strains (FINGERPRINTING METHOD) 01.01.12-31.03.12;

“The studying of antituberculosis activity of new synthesized compounds of tioureide 2-(2–phenylethyl)-benzoic acid” 2010-2012. She is author and co-author of 5 publications and scientific presentations.

Area of expertise: TB microbiology, TB drug resistance, the study of compounds with biological activity.

Languages: Romanian, Russian, English.
Nadejda Turcan was born on June 18, 1986

Mrs. Turcan graduated from the State University of Medicine and Pharmacy “NICOLAE TESTEMITANU” in 2010. She has been working at the Institute of Phthisiopneumology of Moldova as fellow researcher since 2011-present. She has participated in the following projects: “Studying the phenomenon of nosocomial transmission of MDR TB by genotypic analysis of DNA diversity of M.tuberculosis strains (FINGERPRINTING METHOD) 01.01.12-31.03.12; “The studying of antituberculosis activity of new synthesized compounds of tioureide 2-(2–phenylethyl)-benzoic acid” 2010-2012. She is author and co-author of 2 publications and scientific presentations



Area of expertise: TB microbiology, TB drug resistance, the study of compounds with biological activity.

Languages: Romanian, Russian, English.
How does this project relate to our other work?
There have been 4 projects with the topic close to the present project developed by the team from the Institute of Chemistry:

  • 2 Budgetary projects: Ref. № 06.408.030 F, Ref. № 09.820.05.08 GF.

  • 2 Non budgetary - project grant №10884 financed by the International Innovative Nanotechnology Centre of the CIS countries; project The Royal Society International Joint Project Ref. № JP090309.

The projects have been mainly dedicated to the development and study of structure – activity relationships of the new anti-tuberculosis drug substances. The studies performed by Dr.hab. Macaev and collab. have led to discovery of a new group of substances with high anti-mycobacterial activity from the class of 5-aryl-2-thio-1,3,4-oxadiazole derivatives according to the structure-activity relationship and preliminary biological activity studies [1, 2]. Also encapsulation of one new potential anti-tuberculosis substance in β-cyclodextrin has been performed and the obtained results were published [3].



1 patent has been obtained [4] and 1 patent application has been submitted [5] concerning the alkaloids brevicarine and brevicolin obtaining and potential use as anti-tuberculosis substances.
The present project is going to continue the work of the previous projects by evaluation of the activity and toxicity of the investigated substances in the free and nano-encapsulated form. We expect that nano-encapsulation under this project will improve the biological properties of the substances and will make them more attractive for different pharmaceutical companies for the follow-on development.


  1. Macaev, F., Rusu, Gh., Pogrebnoi, S. et al.: Synthesis of novel 5-aryl-2-thio-1,3,4-oxadiazoles and the study of their structure-anti-mycobacterial activities. Bioorg. Med. Chem. 13, 4842-4850 (2005)

  2. Macaev F., Ribkovskaia Z., Pogrebnoi S., Boldescu V., Rusu G., Shvets N., Dimoglo A.,Geronikaki A., Reynolds R. Journal of Bioorganic Chemistry, 2011, 19, 6792 – 6807;

  3. Boldescu V., Bratu I., Borodi Gh., Kacso I., Duca Gh., Macaev F., Pogrebnoi S., Ribkovskaia Z. Journal of Inclusion Phenomena and Macrocyclic Chemistry, 2011. DOI: 10.1007/s10847-011-0091-7 (electronic version);

  4. Macaev F., Stingaci E., Duca D., Duca G. Use of 1-methyl-4-(N-methylaminobutyl-4)-β-carboline as antituberculosis remedy. Moldovan patent №4009 from 15.07.2008;

  5. Macaev F., Şepeli F., Şepeli D., Zveaghinţeva M., Şepeli O., Sucman N., Boldescu V., Duca G. Procedure for obtaining of brevicolin – base from Carex brevicolis D.C. Moldovan patent application №2011 0013 from 02.04.201;.Patent 2012.01.31, BOPI № 1/2012, p. 23-24


2.6 Expected results
What will be done in the framework of this project?
Scientific results:

  • obtaining of new nano-encapsulated entities with potential antituberculosis activity: brevicarin and brevicolin, analogues of traptamin alkaloid from the derivatives of 1,3,4-oxadiazoles an 3-amino-2-chinazolin-4-(3H)-ons;

  • elucidation of the processes of nano-encapsulation of the obtained substances in cyclodextrins, study of the structure and physico-chemical properties of the obtained complexes;

  • incorporation of the obtained nanocomplexes in the alginate-chitosan microparticles;

  • determination of anti-mycobacterial activity of the substances and their nanocomplexes through in vitro studies on the M.tuberculosis strains sensible and resistant to isoniazid and rifampicin;

  • evaluation of toxicity of the substances and their nanocomplexes on laboratory animals, determining DL50


What’s next?
The research results can be used for the follow-up development of the antituberculosis drugs. In the case, if the research results are positive and we manage to find a company interested in their follow-on development and marketing.

In the case if we do not get positive results and no company will be interested to continue research with other entities, we will come with a proposal to submit a common project to one of the funding programs we will have found by then.



2.7 Scope of activities
How will the investigation be organized?
The project will be organized in 5 work packages (see table 1, the work package leaders are written in bold). All the major phases and stages of the project are described in the table 2. It also includes description of the intermediate results and milestones. All the milestones are presented separately in the table 3. Al the deliverables are presented in the table 4.

The relations between the work packages in the project are illustrated in the PERT chart bellow:



Table 1: List of Work Packages


Work package n°

Work package title

Researchers involved

Start month

End month

WP1

Project management

Dr.hab Fliur Macaev

Dr. Valeriu Crudu

Dr. Veaceslav Boldescu


1

12

WP2

Synthesis and extraction

Dr.hab Fliur Macaev

Dr. Serghei Pogrebnoi

Dr. Liudmila Vlad

Marina Zviaghinteva



1

9

WP3

Nano-encapsulation

Dr. Veaceslav Boldescu

Dr. Liudmila Loghina

Dr. Eugenia Stingaci

Vsevolod Pogrebnoi



3

10

WP4

Biological evaluation

Dr. Valeriu Crudu

Elena Romancenco

Ecaterina Stratan

Nadejda Ţurcan



3

12

WP5

Market research

Dr. Veaceslav Boldescu

Dr.hab Fliur Macaev

Dr. Valeriu Crudu


1

12


Table 2: Work Packages description


Work Package number

1

Start month

1

Work Package Title

Project management

Partner organisation involved

ICH






















Objectives

The main objective of WP1 is ensuring of timely and qualitative achievement of the project results through administrative coordination as well as meeting contractual commitments.

The management of the project is based on the following main activities:


  • Administrative and financial management

  • Communication with the STCU

  • Quality assurance

  • Communication and control mechanisms between partners

  • Management support to the researchers involved in the project

The activities of the work package will be divided in 2 tasks.




Description of work
Task 1.1 Administrative, financial management, reporting to the STCU

Task leader: Dr.hab. Fliur Macaev
This task will include control of the project’s progress by ensuring administrative and contractual relationships both within the consortium and with the STCU, as well as verifying progress of work and production of deliverables according to the project time schedule.

The Project Manager (ICH) will maintain the contact with the STCU representatives. As well, he will perform monitoring of the project financial flow and management of any appearing issues, delivery of all types of reports and deliverables, formulation of propositions for possible modifications of the work plan.

The procedures to be applied in the case of the conflicts are going to be approved at the project kick-off meeting.
Researchers responsible for the implementation: Dr.hab. Fliur Macaev, Dr. Veaceslav Boldescu
Task 1.2 Quality and risk management

Task leader: Dr. Valeriu Crudu

The Project Manager (ICH) will coordinate and monitor the work that has to be accomplished in order to meet the project’s objectives and to ensure quality of final results. The Project Manager will establish appropriate quality control & assurance procedures in order to allow maximum flexibility while maintaining a clear distinction of roles and responsibilities of all partners involved. Control procedures will include deliverable and document change control and key milestones in the project and project reviews.

The quality control & assurance procedures are going to be approved at the project kick-off meeting by the Coordination and Management boards.

PM will continuously monitor and re-asses project risks. Special attention will be paid to work packages where risks of high impact will be identified. Risk Management will focus mostly on the process of risk mitigation through proactive management which involves the identification of remedial action for the risks that require active management, segregate those that only require monitoring and record secondary risks that might arise from implementing the risk mitigation plans.


Researchers responsible for the task implementation: Dr. Valeriu Crudu, Dr. Veaceslav Boldescu




Deliverables

D 1.1 Trimestral periodic reports and final project report

D 1.2 Project kick-off meeting

D 1.3 Procedures for the conflicts management




Milestones

M 1.1 Successful realization of the project work packages

M 1.2 Effective conflicts and issues management

M 1.3 Efficient risks management

M 1.4 Efficient quality management



Work Package number

2

Start month

1

Work Package Title

Synthesis and extraction

Partner organisation involved

ICH






















Objectives

The main objective of WP2 is to obtain the substances with potential anti-tuberculosis activity for their following evaluation for biological activity and toxicity under free and nano-encapsulated forms.

The activities of the work package will be divided in 2 tasks:

Task 2.1 Synthesis of oxadiazole and chinazolinon derivatives

Task 2.2 Extraction of alkaloids





Description of work
Task 2.1 Synthesis of oxadiazole and chinazolinon derivatives

Task leader:

This task is aimed at synthesis of at least four 1,3,4-oxadiazole and 3-amino-2-chinazolin-4-(3H)-ons derivatives. These derivatives have been proved to possess high potential for anti-tuberculosis activity on the level of structure-activity relationship and preliminary biological activity studies.

Synthesis of the heterocyclic compounds will be realized based on the available an anthanilic, 3-amine as well as 4-amine benzoic acids. The main step of these syntheses is cyclization of linear derivatives will be realized by comprising both alternative approaches (TMTD/ DMF or CS2/KOH/EtOH). Thus, due to the presence of highly reactive centers (-SH, -CO, NH, -NH2, SNC) in the 5-aryl-2-thio-1,3,4-oxadiazoles and 3-amino-2-chinazolin-4-(3H)-one molecules, a wide number of substances will be obtained with different pharmacophores (including brevicarine and brevicolin alkaloids) via bonding with nucleophilic and electriphilic reagents.
Important phases of this task with include:


  1. determination of the synthesis routes if different than the previously used

  2. synthesis of the substances

  3. purification of the substances

  4. physico-chemical analysis of the obtained substances’ structure

These will be performed as follows:

By the end of the 1st Quarter, a part of the oxadiazole derivatives will have been synthesized and characterized.

By the end of the 2nd Quarter, more oxadiazole derivatives and the chinazolinone derivatives will be obtained and characterized.

By the end of the 3rd Quarter, all the chinazolinone derivatives will be obtained and characterized.
Researchers responsible for the oxadiazole derivatives synthesis and study: Dr. Liudmila Vlad

Researchers responsible for the chinazolinone derivatives synthesis and study: Dr. Serghei Pogrebnoi
Task 2.2 Extraction of alkaloids

Task leader:

This task will include extraction of tow main alkaloids with potential anti-tuberculosis activity: brevicarine and brevicolin. The alkaloids will be extracted following the procedure developed by the Dr.hab Macaev team. For the extraction of the materials the local raw materials will be used. These represent the plants from the Carex genus, the main is Carex brevicolis. The use of renewable local raw materials is an important feature of the project making its results more competitive and sustainable. One of the important phases is collection and preparation of the raw material. This influences the yield of the extraction. The plants for the extraction will be collected in May-June of 2012 to be extracted starting January 2013.

The extraction of the brevicolin will be performed using the method of contra-flow concentration with application of acidulated water and organic solvents. The yield of the method is 2-3 times higher than that of the known methods. The extraction of the brevicarine will be studied and adjusted to obtain higher yields as well.

Important phases of this task with include:



  1. collection and preparation of the raw material for the extraction

  2. extraction of the raw material

  3. purification of the alkaloids

  4. physico-chemical analysis of the alkaloids to prove their chemical structure and nature


Researchers responsible for the brevicarine extraction and study: Marina Zviaghinteva

Researchers responsible for the brevicolin extraction and study: Dr. Liudmila Vlad




Deliverables

D 2.1 Article/patent

D 2.2 Conference presentation




Milestones

M 2.1 10 oxadiazole and chinazolinone derivatives of ready for nano-encapsulation and biological evaluation

M 2.2 Brevicarine and brevicoline ready for nano-encapsulation and biological evaluation




Work Package number

3

Start month

3

Work Package Title

Nano-encapsulation

Partner organisation involved

ICH






















Objectives

The main aim of WP3 is to perform nano-encapsulation of the substances obtained in the WP2 in the host-guest complexes with cyclodextrins. Nano-encapsulation is an important step to improve the anti-tuberculosis activity of the substances. It will improve their water solubility and stability, but most important is potential improvement of their penetration in the mycobacteria due to presence of cyclodextrins. Cyclodextrins are known to extract cholesterol from the mycobacteria cell wall and enhance its penetrability.


In the WP3, tasks are divided according to the level of encapsulation

Task 3.1 Nano-encapsulation of the synthetic derivatives and the alkaloids in cyclodextrins

Task 3.2 Loading of nano-encapsulated substances into the microparticles





Description of work
Task 3.1 Nano-encapsulation of the synthetic derivatives and the alkaloids in cyclodextrins

Task leader: Dr. Veaceslav Boldescu

Nano-encapsulation of the synthetic derivatives and the alkaloids in cyclodextrins will be performed in the water solutions using 2 main techniques and 2 comparing techniques. The main techniques are co-evaporation and lyophilization. Comparative techniques are physical mixture obtaining and kneading. The techniques are described in the scientific methodology sections.

This task will be implemented in several phases:


  • obtaining of oxadiazole complexes

  • obtaining of chinozolinone complexes

  • obtaining of alkaloids complexes

For the complexes obtaining two main types of cyclodextrins will be used: β-cyclodextrin and hydroxypropyl-β-cyclodextrin. The first one is the most used type of the cyclodextrin and it is well suitable for model complex formation. The second, hydroxypropyl-β-cyclodextrin, will be used as main cyclodextrin in the drug formulations being more water soluble and having better biological characteristics.

The main phases of this task are:

By the end of the 1st Quarter the obtaining of the oxadiazole compelxes will be launched, and at least 1 systems will be obtained and characterized.

By the end of the 2nd Quarter the oxadizaole and a part of chinazolinone systems with cyclodextrins will be obtained and characterized.

By the end of the 3rd Quarter the chinazolinone and one of the alkaloids in the system with cyclodextrins will be obtained and characterized, and in the middle of the 4th Quarter the second alkaloid will be characterized in the system with cyclodextrins.
Researchers responsible for the nano-encapsulation of synthetic derivatives and alkaloids in: Dr. Veaceslav Boldescu, Dr. Liudmila Loghina
Task 3.2 Loading of nano-encapsulated substances into the microparticles

Task leader: Dr. Eugenia Stingaci

Microparticulate system for anti-tuberculosis encapsulated substances transport will be obtained on the basis of the controlled jellification induced by the cations of calcium. For this, to the solution of the sodium alginate, which contains cyclodextrins and anti-tuberculosis substances encapsulated in cyclodextrins, solution of the calcium chloride. Afterwards, solution of chitosan will be added and the mixture is stirred for 30 min. Then, it is left for night at the room temperature. Microparticles loaded with the encapsulated substances and the cyclodextrins are recuperated through centrifugation and washed with bi-distilled water.

Only encapsulated substances that will show highest activity from their class will be loaded in the microparticles.

Thus, by the end of the 2nd Quarter, microparticles based on the best performing oxadiazole encapsulated anti-mycobacterial substance will be obtained.

By the end of the 3rd Quarter, microparticles based on the best performing chinozolinone encapsulated anti-mycobacterial substance will be obtained.

By the end of the 4th Quarter, microparticles based on the best performing alkaloid encapsulated in cyclodextrins will be obtained.


Researchers responsible for the loading of nano-encapsulated substances into the microparticles: Dr. Eugenia Stingaci, Vsevolod Pogrebnoi




Deliverables

D 3.1 Article/patent

D 3.2 Conference presentation




Milestones

M 3.1 Nano-encapsulated substances ready for biological evaluation

M 3.2 Microparticles ready for biological evaluation


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