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Progenitors for Antiviral and Tuberculostatic Preparations

#G-1707


Investigation by Prof. T. Khoshtaria's Method of the Synthesis of Tricyclic Indole- and Isatin-Containing Systems with Antiviral and Tuberculostatic Activities” (Synthesis and Wide Screening)

Tech Area / Field

  • BIO-CGM/Cytology, Genetics and Molecular Biology/Biotechnology
  • MED-DID/Diagnostics & Devices/Medicine

Status
3 Approved without Funding

Registration date
19.12.2008

Leading Institute
Georgian Technical University, Georgia, Tbilisi

Collaborators

  • Southern Research Institute, USA, AL, Birmingham\nErweiterte Realschule Saarbrücken -Güdingen, Germany, Saarbrücken

Project summary

The basic statistics of the present-day global "tuberculosis problem" are well known: one-third of the global population is considered infected; 6 million new cases each year; 20% of adult death and 6% of infant deaths are attributable to TB. The increased incidence of drug-resistant tuberculosis certainly highlights the need for new antitubercular drugs. Equally urgent is the need for new antiviral agents, especially with the growing concern for the next influenza pandemic.

The ever-growing resistance of tuberculosis to medicines undoubtedly creates the demand for preparing new antitubercular remedies. “Tuberculosis is the reason for which it is necessary to create medicines of a new generation” – that was the fundamental suggestion made by the participants of the international symposium held in September of 2002 in Bangalore (India) and dedicated to the Day of Tuberculosis (Patrick J. Brennen. Plenary lecture. "International Symposium on "Current developments in drug discovery for tuberculosis", Bangalore, India, 2002.).

We propose to combine the expertise of Georgian and USA scientists to pursue the general goal of developing of a new novel generation compounds with antitubercular and antiviral activity, based on the original indole-containing tricyclic systems - isomeric 6α-pirono-1H-benzo[b]indoles and dioxodihydro-6α-pirono-1H-benzo[b]indoles shown in Description.

Our strategy is based on literature precedents that show that the combination of two pharmacologically active bicyclic systems in one molecule can promote the increase of biological activity of the molecule and expand the spectrum of its pharmacological action.

In the present study, the basic bicyclic system is indole. Since the nature of the second bicyclic system is crucial for the pharmacological activity of tricyclic construction, we have chosen comarine as the bicyclic partner for.

The research team of Prof. T.Khoshtaria has more than 30 years expertise and experience in the synthesis and study of condensed tetracyclic systems. Among the vast number of synthesized heterocyclic compounds, their derivatives of isomeric 6α-pirono-1H-benzo[b]indoles were found to have the most promising tuberculostatic and viral activity.

Several years ago we began collaborating with the US NIH's NIAID-sponsored compound screening programs, the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF) and more recently, the Antimicrobial Acquisition and Coordinating Facility (AACF), which provides us with compound screening services against tuberculosis and 30 viruses (including influenza A and B strains), respectively. More than 50 compounds were sent for preliminary screening. Many of them showed high anti-tubercular in vitro activities and several - high antiviral (IVA (H1N1), IVA (H3N2) and IVB) activity, as we predicted.

All 6 possible isomers of both 6α-pirono-1H-benzo[b]indoles and dioxodihydro-6α-pirono-1H-benzo[b]-indoles - precursors of new heterocyclic systems were originally synthesized by this team, using at the initial stages of their study, classical Fisher's and Sandmeier's reactions, accordingly.

For the proposed project, the following specific tasks will be done:

  1. The preparation of isomeric 6α-pirono-1H-benzo[b]indoles, for the present project, we plan to use an improved a modification of Fisher's method (see Description).and their derivatives, for the present project, we plan.
  2. The preparation of isomeric dioxodihydro-6α-pirono-1H-benzo[b]indoles and their derivatives;
  3. Screening and pharmacological study of the prepared task 1-2 compounds against Mycobacterium tuberculosis H37Rv and Viruses such as Flu A and Flu B.

Synthesis (tasks 1-2) will be carried out by the Georgian team. Pharmacological studies (task 3) will be carried out by the US team.


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