Design, synthesis and preliminary antimicrobial evaluation of n-alkyl chain tethered c-5 functionalized bis-isatins

Authors: SINGH, AMANDEEP - Guru Nanak Dev University; NISHA - Guru Nanak Dev University; BAINS, TRPTA - University Of California; HAHN, HYE - University Of California; LIU, NICOLE - University Of The Pacific; Tam, Christina; Cheng, Luisa; KIM, JONG - University Of California; DEBNATH, ANJAN - University Of California; LAND, KIRKLAND - University Of The Pacific; KUMAR, VIPAN - Guru Nanak Dev University

Submitted to: MedChemComm
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/17/2017
Publication Date: 9/19/2017
Citation: Singh, A., Nisha, Bains, T., Hahn, H.J., Liu, N., Tam, C.C., Cheng, L.W., Kim, J.H., Debnath, A., Land, K.M., Kumar, V. 2017. Design, synthesis and preliminary antimicrobial evaluation of n-alkyl chain tethered c-5 functionalized bis-isatins. MedChemComm. 8(10):1982-1992. https://doi.org/10.1039/C7MD00434F.
DOI: https://doi.org/10.1039/C7MD00434F

Interpretive Summary: Discovering and designing new therapies against infectious diseases is critical to human and animal health. Here, we synthesized a new set of isatin-conjugates compounds with unique chemical compositions and tested them against a number of mucosal protozoal pathogens – including the food- and waterborne pathogens Giardia lamblia and Entamoeba histolytica – as well as the human STI caused by Trichomonas vaginalis, and the free living, waterborne amoeba Naegleria fowleri. We also examined the effect of the new library against the fungus Aspergillus parasiticus. Our results identified several lead compounds against these different eukaryotic pathogens. Since antibiotics often negatively impact the normal flora of a patient, we also screened the chemical library on several known normal flora bacteria and fungi and observed no effect on their growth at the highest concentration used in this study. Taken together, this study shows that several of these compounds are selective for eukaryotic pathogens, and identify possible new leads for drug discovery against mucosal pathogens, including foodborne and waterborne protozoal parasites.

Technical Abstract: A series of N-alkyl tethered C-5 functionalized bis-isatins were synthesized and evaluated for antimicrobial activity against pathogenic microorganisms. The preliminary evaluation studies revealed the compound 4t, with an optimal combination of bromo-substituent at the C-5 position of isatin ring along with propyl chain linker being most active among the synthesized series exhibiting an IC50 value of 3.72 mM against Trichomonas vaginalis while 4j exhibited an IC50 value of 14.8 mM against N. fowleri, more effective than the standard drug miltefosine. The compound 3f with an octyl spacer length was the most potent among the series against Giardia lamblia with an IC50 of 18.4 mM while 3d exhibited an IC50 of 23 mM against Entamoeba histolytica. This library was also screened against the fungal pathogen Aspergillus parasiticus. A number of the compounds demonstrated potency against this fungus, illustrating a possible broad-spectrum activity. Furthermore, an evaluation of these synthesized compounds against a panel of normal flora bacteria and fungi revealed them to be non-cytotoxic, demonstrating the selectivity of these compounds. This observation, in combination with previous studies that isatin is non-toxic to humans, presents a new possible scaffold for drug discovery against these important protozoal pathogens of humans and animals.