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Combined Chemotherapy of Infections

#B-1645


Development of New Effective Pharmaceuticals for Combined Chemotherapy of Infections

Tech Area / Field

  • CHE-SYN/Basic and Synthetic Chemistry/Chemistry
  • BIO-MIB/Microbiology/Biotechnology
  • MED-DRG/Drug Discovery/Medicine

Status
8 Project completed

Registration date
21.05.2008

Completion date
16.02.2010

Senior Project Manager
Gremyakova T A

Leading Institute
Belarussian State University / Institute of Physical Chemical Problems, Belarus, Minsk

Supporting institutes

  • Belarussian Research Institute for Epidemiology and Microbiology, Belarus, Minsk

Collaborators

  • Universitat Leipzig / Institut für Anorganische Chemie, Germany, Leipzig\nInstitut Pasteur, France, Paris\nKatholieke Universiteit Leuven / Rega Institute for Medical Research, Belgium, Leuven

Project summary

The aim of the project is to develop effective chemotherapeutic drugs of a new type based on bioactive metal complexes of phenol derivatives with a broad (antibacterial, antifungal and antiviral) activity spectrum promising for introduction into medical practice.

Formulation of the problem. One of the topical trends of modern medical chemistry is the search for new substances to fight microbial and viral infections which cause more than 20% of overall number of lethal outcomes. Thus, HIV-infection pandemic and widespread use of antibacterial drugs resulted in an increasing number of immunocompromised patients with a high risk of developing invasive mycoses refractory to the standard antifungal therapy [B. E. De Pauw, Eur. J. Clin. Microb. Infect. Dis. 16 (1997) 32; N. Singh, Clin. Infect. Dis. 33 (2001) 1692]. A similar situation is characteristic of other classes of chemotherapeutic drugs as well. In this connection particular emphasis is given to development of combined chemotherapy of infections (using two or more antimicrobial pharmaceuticals simultaneously) and dosage forms of several chemotherapeutic drugs, as well as to development of new pharmaceuticals with a broad activity spectrum [M. Leeb, Nature 431 (2004) 892].

A crucially new method of attacking these fundamental problems is based on the suggestion that in the human body many bioactive compounds (including pharmaceuticals) act as complexing agents, and most of them can exert pharmacological activities only when interacting with biometal ions [Metallotherapeutic Drugs and Metal-Based Diagnostic Agents. The Use of Metals in Medicine / Eds. M. Gielen, E. R. T. Tiekink. Weinheim: Wiley-VCH, 2005]. Thus, functional modifying of biologically active substances and pharmaceuticals by binding them into metal complexes in order to increase their pharmacological effect and minimize their toxicity and side effects seems quite promising. But as for now, there is no extensive studies of properties of metal complexes as potential chemotherapeutic agents with a broad spectrum of activities (antibacterial, antifungal and antiviral). Investigation of metal complexes of phenol-containing ligands, in our view, is a promising field of search for substances of this kind. In deciding on Cu(II), Co(II), Ni(II), Zn(II), Fe(II), Mn(II) and Ag(I) complexes as the subjects of the study the reported results of medical use of bioactive metal complexes were considered [Uses of Inorganic Chemistry in Medicine / Ed. N. P. Farrell. RCS, 1999; Metallotherapeutic Drugs and Metal-Based Diagnostic Agents. The Use of Metals in Medicine / Eds. M. Gielen, E. R. T. Tiekink. Weinheim: Wiley-VCH, 2005]. First, a metal complex may have the lipophilicity higher than that of the inpidual components. Second, due to the peculiarities of structure and other characteristics metal complexes are able to realize several mechanisms of therapeutic action involving such potential biological targets as enzymes, membranes, DNA, RNA, proteins, thus promoting possibilities to produce pharmaceuticals on their basis with a broad spectrum of action and making it possible to solve the problem of resistance of pathogenic microorganisms. The main aim of the project is to find the relationship between the bioactivity of ligands and their complexes with transition metals and their composition and structure and then to synthesize compounds with tailored properties.

The effect of the project on the progress in the field of development of novel antimicrobial and antiviral drugs: new active substances (diphenol and aminophenol derivatives and metal complexes thereof) will be produced, which are able to effectively inhibit bacterial, fungal and viral infections due to simultaneous realization of several mechanisms of pharmacological action involving different biological targets.

Participants of the project: The Research Institute for Physico-Chemical Problems of the Belarusian State University (RI PCP BSU) and State Institute The Research Institute for Epidemiology and Microbiology (SI RIEM). Research workers of RI PCP BSU are widely experienced in synthesizing and testing antioxidants and stabilizers for materials used in weapon technologies. As of now, their scientific work is related to synthesis of inhibitors of various homolytic processes, investigation of their physico-chemical and pharmacological properties. Among the participants of the project there are scientists specializing in the chemistry of coordination compounds, electrochemistry, virology and microbiology. Research workers of SI RIEM took part in a number of classified comprehensive scientific research works financed by the Ministry of Defence of the USSR, dealing with synthesis and investigation of activities of compounds against viral infectious agents that were of concern in developing bacteriological weapon. The scientific adviser of the project, Prof. O.I. Shadyro, is a leading specialist in the field of radiation chemistry and chemistry of free radicals, who has experience in carrying out complex investigations to create novel pharmaceuticals. The project manager, Dr. N.V Loginova., also took part in a number of classified comprehensive studies financed by the Ministry of Defence of the USSR.

Expected Results and Their Application.

Category of technology development is applied investigations.Solving the 4 fundamental problems will result in the following:

  • The procedures will be developed for synthesizing derivatives of sterically hindered diphenols and aminophenols and their metal complexes;
  • The composition, structure and physico-chemical characteristics of ligands and their metal complexes will be determined, and antioxidant and radical-inhibiting properties of these compounds will be investigated;
  • Pharmacological screening of bioactive phenolic derivatives and their metal complexes will be carried out; the dependence of pharmacological activity on their composition and structure will be evaluated;
  • The criteria of selection will be stated to reveal the compounds promising for creating novel chemotherapeutic medicines with a broad spectrum of pharmacological activity.

The fulfillment of the project is suggested to result in development of relatively cheap, effective chemotherapeutic agents of low toxicity, holding promise for introduction into medical practice.

The scientific value of the project lies in the fact that the relationship will be found for the first time between the structure of the ligands and metal complexes synthesized and their activity against a wide variety of bacteria, yeasts, fungi and viruses strains.

Application of the project results. The findings of the project are planned to be employed in the Public Health Service System of the Republic of Belarus to produce pharmaceutical dosage forms and carry out clinical tests thereof. Thus, the bioactive phenolic derivatives and their metal complexes are planned to be used for modifying the antiherpetic pharmaceutical “Butaminophen” (produced in Belarus) in order to broaden the spectrum of its therapeutic action and overcome the possible resistance of microorganisms.

Meeting ISTC Goals and Objectives. The project fits the goals and objectives of ISTC as:

  • it gives the participants of the project who took part in the studies related to weapons technologies the chance to reorient so as to solve the purely humanistic problem of creating new medicines;
  • the experimental data obtained together with foreign specialists working in the fields of chemistry, biology and medicine will promote integration of the participants of the project into the inernational scientific community;
  • it is aimed at solving practical problems for peaceful purposes in the field of Public Health Service, materials science;
  • it supports the change-over of the participants of the project towards market economy by selling licenses connected with “know–how” used in the search for new pharmacologically active substances, as well as licenses for synthesis of substances.

Scope of Activities. The work on the project is to be completed in 3 years, because the project is manifold and requires large-scale investigations in the field of purposeful synthesis of numerous derivatives of diphenols and aminophenols (about 50) and their metal complexes (about 50), examination of their physico-chemical, antibacterial, antifungal and antiviral properties. In this connection the teams (23 participants) from RI PCP BSU and RIEM will be recruited for the work.

Role of Foreign Collaborators. The following forms of participation in the project were agreed upon with the collaborators:

  • carrying out joint (with collaborators) scientific research;
  • participation in joint meetings;
  • scientific information exchange.

Technical Approach and Methodology. The approach to be used in carrying out the project is a systematic and purposeful study allowing one to find out the cause-and-effect relationship between the structure of the substances and their antimicrobial and antiviral activities. The preliminary findings obtained by the participants of the project evidence that among derivatives of diphenols and aminophenols, as well as their metal complexes, there are substances effectively suppressing the processes of reproduction of viruses of herpes, flu and HIV, which also demonstrate antimicrobial activity [Loginova N.V. et al. Centr. Eur. J. of Chem. 4 (2006) 440; Loginova N.V. et al. Polyhedron 25 (2006) 3603; Loginova N. V. et al. Bioorg. Med. Chem. Lett. 16 (2006) 5403]. The same substances affect also various free-radical processes. In the preliminary investigation effects were found which verified the suggestion that there was a sertain correlation between redox properties of metal complexes and their bioactivities, which may be due to redox effect on electron-transport cell systems. The technical solution of the problems will be provided by involving modern synthetic procedures and physico-chemical methods of investigation (chromatography, UV-Vis, IR and ESR spectroscopy, voltammetry, conductometry, potentiometry). Microbiological investigation will be carried out according to standard recommendations on determining susceptibility of microorganisms to chemical compounds by the method of serial dilutions on several tens of strains of bacteria, yeasts and fungi. Examination of the antiviral properties will be carried out in experiments on monolayer structures of cells with viruses of herpes, flu and HIV. The substances which have demonstrated the most pronounced antiviral activity on cell cultures will be also tested under conditions of experimental virus infections of laboratory animals. Standard methods of microbiology and virology will be employed, according to which the team of project participants is accredited by the Belarus National Agency of Standards.


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