Bioisosteres and Methodology

Basic information

Research includes development of novel synthetic methodology; identification of unique biosisosteres with applicability in pharmaceutical agents and conception and preparation of novel anti-infective agents with activity against multidrug-resistant pathogens.

Bicyclo[1.1.1]pentane (BCP) Biosisosteres and Methodology

We have had a longstanding interest in the development of new synthetic methodology to enable the facile preparation of BCP compounds.   Currently, we are investigating the utility of palladium-mediated cross-coupling reactions of novel BCP derivatives to furnish useful elaborated intermediates.  

From a more strategic perspective, we are attracted to the BCP moiety as a bioisosteric replacement for other subunits in biologically active substances, taking advantage of its unique electronic properties, good metabolic stability, and highly condensed, sterically compact nature.  For example, some years ago we reported the preparation of potent quinolone antibacterial agent U-87947 from bicyclo[1.1.1]pentylamine.  U-87947 incorporates a BCP isostere in place of the usual cyclopropane or aromatic/heteroaromatic ring system found at the N1 position of most successful quinolone antibacterial agents.

A long-term goal is to apply some of our newly developed methodology and incorporate the BCP ring system into additional pharmaceutical agents selected from several therapeutic areas.  However, our current focus is on the rational design and synthesis of BCP-substituted antibacterial agents.  Targeted compounds will need to be synthesized and tested for antibacterial activity, with good coverage of problematic multidrug-resistant bacterial pathogens a priority.

Identification of Novel Anti-infective Agents

The preparation of new anti-infective agents, especially antibacterials, through classical synthetic or semi-synthetic approaches is being pursued on an opportunistic basis.  A recent effort in this area involved an attempt to functionalize a carbon on a known antibacterial scaffold that had never before been successfully modified.  Success in this regard would provide privileged compounds with hopefully improved characteristics. 

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Michael Barbachyn

Michael Barbachyn

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