Series 3: A tricyclic antifungal drug devlopment project

Advantages:

• Tricyclic class drugs show a large spectrum of activity against both fungi and amoeba (including those that cause some NTD's)
• Extremely low cost and straightforward to produce (only 2 or 3 steps from common materials) (1 kilo of phenothiazine is less than 100 usd from SA)
• Suspected multiple mechanisms of action including calmodulin and lipid synthesis disruption makes resistance unlikely ( https://pubs.acs.org/doi/10.1021/acsinfecdis.7b00157 and https://academic.oup.com/mmy/article/53/8/890/982579 and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815111/ )
• Lipophilic to penetrate into fungal grain
• t½ varies quite a bit but is generally long (e.g 30h t½ for chlorpromazine and ~10h t½ for trifluoperazine)
• This class of drugs has been used in clinical antimicrobial experiments a handful of times: (E.G https://doi.org/10.1016/S0140-6736(83)91769-5 and https://doi.org/10.1086/379020 )

Disadvantages:

• Some tricyclic drugs may cause a tetracycline-like photosensitivity in vivo (We will need to research this more)
• Water solubility is very variable
• Myelosuppression is a rare side effect reported from long term use from some but not all drugs in this class (We will need to research this more)
• Some tricyclic class drugs come with some with some rather unpleasant side-effects