Metal-Chelating and Metal-containing compounds with anti fungal properties. Thoughts?

[fantasy121]

@OpenSourceMycetoma/corecontrib

Just leaving this post here for structures, literature resources and suggestions of compounds with metals. Please share in the comments.

[bebi78]

@fantasy121 @dmitrij176 Here are some links to metal complexes of azoles. I have also published some papers about piano stool Ru complexes with pyridine ligands (analogously to the ruthenium paper link below). It is a simple reaction of 1 eq. of pyridine compound with 0.5 eq. of the commercially available Ru dimer [RuCl2(p-cymene)]2 in DCM or acetone at r.t. for a few hours. The product can be simply precipitated and washed with hexane in most cases.

https://pubs.acs.org/doi/10.1021/jm300070h https://pubs.rsc.org/en/content/articlelanding/2022/dt/d2dt00411a https://www.sciencedirect.com/science/article/pii/S0162013412001407

[bebi78]

@wwjvdsande Sometimes it also helps to add just a simple copper or iron salt to the azole in order to increase activity.

https://pubs.rsc.org/en/content/articlelanding/2019/DT/C9DT00642G https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208471

[MFernflower]

Auranofin - it's expensive but a decent antimicrobial

https://www.mdpi.com/1420-3049/25/21/5075/htm

[MFernflower]

Despite the unpleasant side effects have the antimony based drugs used to treat kala-azar been tested against eumycetoma? @bebi78 @wwjvdsande

It may very well be a lower dose of said drug could be used to kill the fungus - would be somewhat convenient as many Indian physicians already have access to said drugs for kala-azar treatment

[bebi78]

@MFernflower @wwjvdsande These antimonials are Sb(V) prodrugs which need reduction to active Sb(III) to kill the parasite. They are mainly active against Leishmania amastigotes because the host cells/macrophages reduce the Sb(V) to Sb(III) which kills the intracellular amastigotes then. Parasitic uptake of the Sb(III) by porins is important in this process, too. So the question is whether eumycetoma has similar biological processes in the fungal cell or environment/grains?

[bebi78]

@wwjvdsande Has auranofin been part of the MMV or DNDi pandemic response box?

[bebi78]

@MFernflower @wwjvdsande Good news. I have some mg of auranofin left I can send. Auranofin has an interesting mechanism targeting cysteine-rich proteins in the fungal mitochondria (Mia40). In addition, I have received nootkatone and maritima from IFF today. @MA-Jjingyi Thanks for providing the first results of the new cinnamides.

[bebi78]

@wwjvdsande I have dispatched a new package today containing the two IFF perfumes nootkatone and maritima, the gold complex auranofin, a Ru complex of maritima, and Bengal Rose B (photodynamic therapy). IFF.auranofin.docx

[bebi78]

@fantasy121 @dmitrij176 @mattodd Here is a link to a review about metal-based antifungals:

https://pubs.rsc.org/en/content/articlelanding/2021/cs/d0cs00945h

[bebi78]

@fantasy121 @dmitriy @mattodd I made the title compound of this article, viz. (p-cymene)Cl2Ru(II) complex of clotrimazole: https://pubs.acs.org/doi/10.1021/jm300070h @TariqAyub tested it and some new analogs with bifonazole and climbazole against parasites, and the Ru complexes were much more antiparasitic than the metal-free azoles. Now there is the question if there is interest to test the compounds against fungi/eumycetoma @wwjvdsande ? @TariqAyub was struggling to get fungal strains for testing in his lab. Is there any progress? As mentioned previously, the synthesis is quite simple and should also work for fenarimols.

[bebi78]

@fantasy121 @dmitrij176 @MFernflower @mattodd Here is the link to my recently published paper about Ru(II) azoles. Maybe fenarimol complexes will have increased activity, too. https://www.sciencedirect.com/science/article/pii/S0020169324000951