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New Indol-Containing Condensed Tetracyclic Systems

#G-865


New Indol-Containing Condensed Tetracyclic Systems as Substances with Potential Antitubercular Activity: Synthesis and Screening

Tech Area / Field

  • CHE-SYN/Basic and Synthetic Chemistry/Chemistry
  • MED-DRG/Drug Discovery/Medicine

Status
8 Project completed

Registration date
29.03.2002

Completion date
04.07.2006

Senior Project Manager
Weaver L M

Leading Institute
Georgian Technical University / The Laboratory of Synthesis of Heterocyclic Compounds, Georgia, Tbilisi

Collaborators

  • Southern Research Institute, USA, AL, Birmingham

Project summary

The aim of this project is the development of a new novel generation of bio-active substances, especially compounds with antitubercular activity, based on original indole-containing tetracyclic systems – isomeric dioxodihydro-1H-benzo[b]thiophene indoles:

and benzo[b]thiophene indoles:

Fig. 2.

The compounds above were first synthesized by Prof. T. Khoshtaria and coworkers and will be used as “lead compounds” for new targets, are anticipated to have at least tuberculostatic activity.

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 tetracyclic construction, we chose benzo[b]thiophene as the bicyclic partner for the reasons given below.

The research team of Prof. T. Khoshtaria has more than 25 years expertise and experience in the synthesis and study of condensed tetracyclic systems. Their results are in good agreement with the concept of the combination of two bicyclic systems in one molecule, stated above. Their tetracyclic compounds include many that have a wide range of physiological activity including bactericidal, fungicidal, neurotropic, psychotropic, anti-tumor, spasmolytic, vasodilator, etc. activities were discovered.

Among their vast number of synthesized heterocyclic compounds, derivatives of isomeric benzo[b]thiophene indoles were found to have the most promising tuberculostatic activity.

Pharmacological studies (limited because they were ceased after disintegration of the former USSR) of several derivatives of tetracyclic benzo[b]thiophene indoles, showed the influence of both the configuration of tetracyclic system and the nature of substituent(s) on tuberculostatic activity of the compounds. For example, for the benzo[b]thiophene indoles with carboxylic group substituents, those with linear configurations showed higher activities, while those of the same configuration, but with formyl substituent had no activity. Interestingly, derivatizing the formyls as thiosemicarbazides increased their activities noticeably.

The decisive pharmacological role of second bicyclic system was clearly demonstrated for benzo[b]thiophene indoles and their derivatives, which displayed much higher antitubercular activity than the O-(benzofuran as the second bicyclic system) and N-containing (indole itself as the second bicyclic system) analogues, with the latter showed the lowest activity.

Thus, Prof. T. Khoshtaria and coworkers have systematically shown that tetracyclic systems, and especially isomeric benzo[b]thiophene indoles and dioxodihydro-1H-benzo[b]thiophene indoles are very promising as “lead compounds” for a new generation of tuberculostatic compounds. All 6 possible isomers of both benzo[b]thiophene indoles and dioxodihydro-1H-benzo[b]thiophene indoles (see Figs. 1 and 2 above) – 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.

In spite of the success achieved, the Fisher’s classical approach to the synthesis of indole-containing heterocyclic systems is not be considered as an optimal approach to these compounds, because it leads to the formation of isomer mixtures of isomers whose isolation and purification require laborious and tedious column chromatography that, limit the yields of each isomer. At the initial stages of creating new tetracyclic precursors, the use of these methods was unavoidable because more effective methods for their synthesis were not yet available. As a result, yields of the target products (unsubstituted benzo[b]thiophene indole precursors) were rather low, limiting our ability to obtain new, potentially bioactive derivatives for a wide and systematic pharmacological study.

For the present project, we plan to use an improved synthesis for isomeric benzo[b]thiophene indoles, a modification of Fisher’s method (see Project Description).

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

1. The preparation of isomeric dioxodihydro-1H-benzo[b]thiophene indoles;


2. The preparation of isomeric benzo[b]thiophene indoles using modified methods of indole synthesis;
3. The synthesis of potentially bioactive compounds – derivatives of isomeric benzo[b]thiophene indoles;
4. The synthesis potentially bioactive compounds – derivatives of isomeric dioxodihydro-1H-benzo[b]thiophene indoles.
5. Screening of the prepared compounds against Mycobacterium tuberculosis H37Rv for the pharmacological study of the substances prepared according to tasks 1-4

Synthesis (Tasks 1-4) will be carried our by the Georgian team.

Pharmacological studies to determine the antitubercular activities of our compounds will be carried out by the Tuberculosis Antimibcrobial Acquisition & Coordinating Facility (TAACF) Program, operated by Southern Research Institute, P.O. Box 55305, Birmingham, AL 35255-5305 USA. This program is funded through a research and development contract with NIAID (the National Institute of Allergy and Infectious Diseases of the U.S. National Institutes of Health). Dr. Cecil D. Kwong will be our TAACF contact for this work.


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