MMV665943

[wwjvdsande]

The first screenings in the MycetOS project included the Pathogen Box and the Stasis Box from MMV. The Malaria Box was not screened. Others screened the Malaria Box against other fungal pathogens and recently Jung et al. published their findings on screening the Malaria Box against Cryptococcus neoformans (https://msphere.asm.org/content/3/2/e00537-17). One of the compounds, compound MMV665943 (IUPAC name 4-[6-[[2-(4-aminophenyl)-3H-benzimidazol-5-yl]methyl]-1H-benzimidazol-2-yl]aniline) was found to have potent antifungal activity. The molecule was named 262 in this paper and was shown to be fungicidal against C. neoformans. Fluconazole was fungistatic. It had relatively low toxicity against mammalian cells and it was fluorescent which allows to follow its penetration into the fungal cell. Next to C. neoformans, the molecule also had activity against Lomentospora prolificans, Cryptococcus gattii and Candida albicans and fluconazole resistant isolates of these species. Due to its fluorescent and fungistatic nature, would this be an interesting molecule to look further into? Would it also be active against Madurella mycetomatis? And are there derivatives of this molecule available as well?

[drc007]

@wwjvdsande

It looks like the structure is a dimer linked by a single carbon. The monomer is available from multiple vendors. http://www.chemspider.com/Chemical-Structure.306587.html

http://akoscompounds.de/catalogue/?IDNUMBERS=AKOS000104179 https://www.keyorganics.net/catalog/product/view/id/808923 https://mcule.com/MCULE-4481213681/

Let me know if you need alternative vendors.

[MFernflower]

It appears that this molecule looks rather similar to various DNA binding dyes (the Hoechst class of dyes) so this molecule might possibly have PAINS issues: @drc007 @wwjvdsande

However - I am still very interested in this molecule!

[MFernflower]

@drc007 ENAMINE limited stocks an interesting monomer as-well but as there site is undergoing upgrades as of the time I am writing this comment I can only leave the link: https://www.enaminestore.com/catalog/EN300-25549

(It's 84 usd per 500 milligrams)

[wwjvdsande]

That's interesting.

[MFernflower]

@wwjvdsande If you can obtain a good quantity of MMV665943 I think it would be interesting to do some florescence microscopy of cells (perhaps Acanthamoeba?) treated with the drug so we can see if the drug localizes to the nucleus thus confirming or denying my suspicion of it being a dsDNA binder

[wwjvdsande]

@MFernflower. I already received the compound from MMV. My initial experiment will be to determine if it inhibits to know at which concentrations there is still some growth. I was planning to do some fluorescence microscopy on the hyphae. There are stains I could use to visualise the nucleus, the cell wall and the mitochondria of the fungal cell.

[MFernflower]

Sounds good @wwjvdsande - if my hunch is correct you should be able to see the nucleus glow just from the drug alone with no additives needed!

[MFernflower]

Recently isolated bacterial natural product has some similarity to MMV665943 https://www.mdpi.com/1660-3397/17/1/9 @drc007

@mattodd @wwjvdsande perhaps could request samples from authors?

[wwjvdsande]

We tested MMV665943 against M. mycetomatis. Unfortunately, MMV665943 did not inhibit the growth of M. mycetomatis at a concentration of 16uM or lower. Higher concentrations were not tested.

[mattodd]

Hi @wwjvdsande could you please add this result to the MycetOS list of data here? In the first tab labelled MyOS compounds.

For the experiment is there a primary record you need to share, containing relevant data? If we imagine for a moment that in a year or so someone is browsing the excel sheet and sees this result they may think "where does this datapoint come from" and we have no back link from that entry to this page. We should try to avoid such "orphan" entries. One possibility is that we enter the URL for this page into the relevant cell in the Notes column, column C. We should, in general, be sharing lab notebook entries for all experiments, if they exist.

[MFernflower]

@wwjvdsande @mattodd This is a bit unrelated but have we considered screening the MMV pandemic response box against mycetoma?

[wwjvdsande]

@MFernflower @MFernflower I indeed ordered the MMV pandemic response box. When the box arrives and is tested I will update it here. I just returned from Sudan and will update all raw data in the excel sheet as well. @mattodd can you post it online? I still don't know how I can do that. Sorry, I'm not that good with computers.

[mattodd]

Hi @wwjvdsande - so all the data in MycetOS are in the online sheet here. You should be able to add directly to it. I'd guess we'd want the data in the "MyOS Compounds" sheet.

[MFernflower]

Perhaps we can get the IC50 of this drug vs the fungus (>16 micromole) into pub chem and thus close this repo? I never submitted to pub chem so no idea what that all entails @mattodd

[MFernflower]

@wwjvdsande This is a bit unrelated but if you can get your hands on decoquinate it would be interesting to test against eumycetoma as it's thought to interact with the mitochondrial bc1 complex

https://www.sciencedirect.com/science/article/pii/S1367593118301480

[MFernflower]

https://en.wikipedia.org/wiki/Dimazole This is an interesting molecule with some minor similarity to MMV665943

Thoughts @drc007

[drc007]

@MFernflower Dimazole is a known azole fungicide, but since MMV665943 was not active I'm not sure it is worth pursuing.

[MFernflower]

@wwjvdsande have the statins been screened VS madurella? They were originally isolated from oyster mushrooms as a way of killing fungal competitors

[wwjvdsande]

@MFernflower Madurella has been screened for the pathogen and stasisbox, azoles, echinocandins, terbinafine, amphotericin B, flucytosine, artemisinin and tea tree oil (I hope I did not leave anything out). Not specially against the statins. Many of the ascomycetes also produce them.

[MFernflower]

This is a pretty tough fungus it seems - way more malicious then the saprobic fungi I normally study as a hobby @wwjvdsande

Have we ever screened our fenarimol derivatives against P. Boydii ? That species is what nightmares are made of!

[wwjvdsande]

It is indeed a tough fungus. We did not screen against _P. _boydii__ It is a known causative agent of mycetoma too. In contrast to madurella mycetomatis it forms white grains.

[MFernflower]

Sorry for the late response @wwjvdsande I was more interested in the blood infections caused by P. Boydii - I tend to think of the fenarimols not just for Madurella but for all of the human pathogenic Pyrenomycetes

[MFernflower]

@cdsouthan Perhaps we can get the biological assay data put into public data bases and then move the screening data to the "other molecules" repo and then delete this repo?