Highly potent 1H-1,2,3-triazole-tethered isatin-metronidazole conjugates against anaerobic foodborne, waterborne, and sexually-transmitted protozoal parasites

Authors: KUMAR, SUMIT - Guru Nanak Dev University; BAINS, TRPTA - University Of California; KIM, ASHLEY - University Of California; Tam, Christina; Kim, Jong Heon; Cheng, Luisa; LAND, KIRKWOOD - University Of The Pacific; DEBNATH, ANJAN - University Of California; KUMAR, VIPAN - Guru Nanak Dev University

Submitted to: Frontiers in Cellular and Infection Microbiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/9/2018
Publication Date: 10/30/2018
Citation: Kumar, S., Bains, T., Kim, A., Tam, C.C., Kim, J., Cheng, L.W., Land, K.M., Debnath, A., Kumar, V. 2018. Highly potent 1H-1,2,3-triazole-tethered isatin-metronidazole conjugates against anaerobic foodborne, waterborne, and sexually-transmitted protozoal parasites. Frontiers in Cellular and Infection Microbiology. 8:380. https://doi.org/10.3389/fcimb.2018.00380.
DOI: https://doi.org/10.3389/fcimb.2018.00380

Interpretive Summary: Foodborne, waterborne, and sexually transmitted parasitic infections like amebiasis, giardiasis, and trichomoniasis are major health threats. The FDA has approved various types of nitro-imidazoles such as ornidazole, benznidazole and secnidazole -- and these are widely used medications against these infections. However, many of these drugs have lower efficacies than metronidazole (MTZ). MTZ is the current drug of choice for amebiasis, giardiasis and trichomoniasis but it has several adverse effects and potential resistance is a concern. In order to develop alternative potential drugs, a chemical library of metronidazole-isatin conjugates were synthesized and evaluated for their amebicidal, anti-giardial, and anti-trichomonal potential. Most of the synthesized conjugates exhibited comparable activities with that of the standard drug MTZ against Trichomonas vaginalis and Tritrichomonas foetus while better activities were observed against Entamoeba histolytica and Giardia lamblia. Several compounds were 2-3 folds more potent than MTZ against E. histolytica and 8-16 folds more potent than MTZ against G. lamblia. These newly synthesized compounds could serve as platforms for new drug discovery against these human pathogens.

Technical Abstract: Parasitic infections like amebiasis, trichomoniasis, and giardiasis are major health threats with their widespread harmful consequences in tropical and subtropical regions of the world. FDA approved various types of nitro-imidazoles such as ornidazole, benznidazole and secnidazole are widely used medications against anaerobic infections but have lower efficacies than metronidazole (MTZ). MTZ is the current drug of choice for amebiasis, giardiasis and trichomoniasis but it has several adverse effects and potential resistance is a concern. In order to develop alternative antimicrobials, a library of 1H-1,2,3-triazole-tethered metronidazole-isatin conjugates has been synthesized using Huisgen’s azide-alkyne cycloaddition reaction and evaluated for their amebicidal, anti-trichomonal and anti-giardial potential. Most of the synthesized conjugates exhibited comparable activities with that of the standard drug MTZ against Trichomonas vaginalis and Tritrichomonas foetus while better activities were observed against Entamoeba histolytica and Giardia lamblia. Conjugates 9d and 10a were found to be 2-3 folds more potent than MTZ against E. histolytica and 8-16 folds more potent than MTZ against G. lamblia. Both these compounds were more toxic to E. histolytica and G. lamblia than a human cell line. Further analysis of these compounds on normal flora bacteria did show inhibitory activity, demonstrating their specific anti-protozoal effects.