OSTB Series4: OpenCyclams

In 2016, Mingfeng Yu, Gaya Nagalingam and co-workers reported a new class of compounds with potent activity against drug-resistant Mycobacterium tuberculosis (Mtb): metal-cyclam complexes with pendant aromatic groups. [Ref.] Further work on this class of anti-tubercular compounds focussed on molecules built around a cyclam scaffold, with an array of hydrophobic pendant groups including naphthalimide, naphthalene and functionalised benzene derivatives. [Ref.] While some of these have shown good potency, with MIC (minimum inhibitory concentration) values as low as 1.56 µM against Mtb, their high molecular weight and low water solubility remain an issue.

More recent work has revealed that simple linear polyamine analogues with naphthalene pendant groups have similar activity – see lead compound JB60-2B. These compounds are easier to work with synthetically, and look to have improved pharmacokinetic properties.

We now present these linear amines as OSTB_Series 4_OpenCyclams. This series of compounds will be built on linear polyamines with varying chain length, number and position of N atoms and attached pendant groups, and type of pendant groups.

Series 4A: with simple naphthalene-derived pendants, varying the length of the linker chain, number and position of N atoms and pendant groups and optimise activity.

Series 4B: applying reagent-based diversity-oriented synthesis (DOS) on the linear hexadiamine scaffold to produce a series of molecules with pendant groups that cover a broad range of chemical space, readily accessible from relatively similar linear polyamine substrates.

Find out more

If you want to get involved, head over to the Wiki tab to find out more about open-source drug discovery, how to use GitHub, and the status of this project.