Skip to main content
ARS Home » Pacific West Area » Albany, California » Western Regional Research Center » Foodborne Toxin Detection and Prevention Research » Research » Publications at this Location » Publication #395710

Research Project: Novel Methods for the Mitigation of Human Pathogens and Mycotoxin Contamination of High Value California Specialty Crops

Location: Foodborne Toxin Detection and Prevention Research

Title: Synthesis and in vitro antiprotozoal evaluation of novel metronidazole–schiff base hybrids

item BETECK, RICHARD - Northwestern University
item ISAACS, MICHELLE - Rhodes University
item LEGOABE, LESETJA - Northwestern University
item HOPPE, HEINRICH - Rhodes University
item Tam, Christina
item Kim, Jong Heon
item PETZER, JACOBUS - Northwestern University
item CHENG, LUISA - Former ARS Employee
item QUIAMBAO, QUINCEL - University Of The Pacific
item LAND, KIRKWOOD - University Of The Pacific
item KHANYE, SETSHABA - Rhodes University

Submitted to: Archive of Pharmacy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/3/2022
Publication Date: 3/1/2023
Citation: Beteck, R.M., Isaacs, M., Legoabe, L.J., Hoppe, H.C., Tam, C.C., Kim, J., Petzer, J.P., Cheng, L.W., Quiambao, Q., Land, K.M., Khanye, S.D. 2023. Synthesis and in vitro antiprotozoal evaluation of novel metronidazole–schiff base hybrids. Archive of Pharmacy. 356(3). Article 2200409.

Interpretive Summary: Trichomoniasis is a neglected venereal infection affecting almost 276 million people worldwide, with Africa and the Americas being the most affected regions. Treatment of Trichomoniasis is based on metronidazole and tinidazole drugs. These agents are effective and safe at low doses required to treat susceptible strains of the parasite. However, serious side effects arise when high doses are used to control metronidazole tolerant and resistant strains of Trichomonas vaginalis. This leads to non-compliance and subsequent treatment failure. Presently, metronidazole tolerant and overt resistant strains of T. vaginalis present a real challenge as there is no alternative drug to metronidazole. In this investigation, novel molecules were generated and tested against T. vaginalis where the metronidazole structure is covalently linked to a Schiff base. The synthesized compounds were tested further for their efficacy against foodborne bacterial and human fungal pathogens.

Technical Abstract: Treatment of Trichomoniasis rely solely on metronidazole and tinidazole, with metronidazole being the mainstay therapy. This study was aimed at generating novel molecules wherein the metronidazole structure is completely conserved and covalently linked to a Schiff base to generate compounds of the general structure, using simple and cheap synthetic transformation. The redox potential around the nitroimidazole ring of metronidazole is crucial for its activation. It’s determined that the low molecular weight of metronidazole (171 Da) couple with its mode of action makes it an ideal fragment that can be engineered via chemical synthesis to generate novel compounds with potent activities against T. vaginalis. The synthesized compounds were also evaluated for their anti-microbial activities against the foodborne pathogens Salmonella enterica, Listeria monocytogenes, as well as the laboratory strain E. coli K-12 and the commensals Lactobacillus acidophilus, Lactobacillus rhamnosus LGG, and Lactobacillus reuteri in the disc diffusion assay. No anti-bacterial activities were observed at 100 microM compound concentrations along with the negative vehicle control. The antibiotic positive controls showed varying effects on the different bacterial strains. The compounds were examined further for the antifungal activities against Aspergillus fumigatus AF293 and Candida albicans ATCC 10231, causative agents for the invasive aspergillosis and candidiasis, respectively, via zone of inhibition bioassay. It’s determined that the compounds possessed very limited antifungal activity at up to 20 mM (maximum strength examined).