Background:
With few exceptions, existing tuberculosis drugs were developed many
years ago and resistance profiles have emerged. This has created a need for new drugs with discrete
modes of action. There is evidence that tuberculosis (like other bacteria) is susceptible to
oxidative pressure and this has yet to be properly utilised as a therapeutic approach in a manner
similar to that which has proven highly successful in malaria therapy.
Objective:
To develop an alternative approach to the incorporation of bacterial siderophores that
results in the creation of antitubercular peroxidic leads for subsequent development as novel agents
against tuberculosis.
Methods:
Eight novel peroxides were prepared and the antitubercular activity (H37Rv) was compared
to existing artemisinin derivatives in vitro. The potential for toxicity was evaluated against
the L6 rat skeletal myoblast and HeLa cervical cancer lines in vitro.
Results:
The addition of a pyrimidinyl residue to an artemisinin or, preferably, a tetraoxane peroxidic
structure results in antitubercular activity in vitro. The same effect is not observed in the absence
of the pyrimidine or with other heteroaromatic substituents.
Conclusion:
The incorporation of a pyrimidinyl residue adjacent to the peroxidic function in an
organic peroxide results in anti-tubercular activity in an otherwise inactive peroxidic compound.
This will be a useful approach for creating oxidative drugs to target tuberculosis.
Effects of module number and firing condition on charge thermal safety in gun chamber