Cinnamoyl-oxaborole amides: Synthesis and their in Vitro biological activity

Authors: GUMBO, MAUREEN - Rhodes University; BETECK, RICHARD - Rhodes University; MANDIZVO, TAWANDA - Rhodes University; SELDON, RONNET - University Of Cape Town; WARNER, DIGBY - University Of Cape Town; HOPPE, HEINRICH - Rhodes University; ISSACS, MICHELLE - Rhodes University; LAMING, DUSTIN - Rhodes University; Tam, Christina; Cheng, Luisa; LIU, NICOLE - University Of Cape Town; LAND, KIRKWOOD - University Of The Pacific; KHANYE, SETSHABA - Rhodes University

Submitted to: Molecules
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/7/2018
Publication Date: 8/15/2018
Citation: Gumbo, M., Beteck, R.M., Mandizvo, T., Seldon, R., Warner, D.F., Hoppe, H.C., Issacs, M., Laming, D., Tam, C.C., Cheng, L.W., Liu, N., Land, K.M., Khanye, S.D. 2018. Cinnamoyl-oxaborole amides: Synthesis and their in Vitro biological activity. Molecules. 23(8):2038. https://doi.org/10.3390/molecules23082038.
DOI: https://doi.org/10.3390/molecules23082038

Interpretive Summary: With the increase in drug resistant microorganisms, the discovery of new treatments against microbial diseases is imperative to maintaining human and animal health. In this study, we synthesized a novel set of amide-based compounds and tested them against three widespread microbial diseases­tuberculosis, malaria, and trichomoniasis. Our results identified several lead compounds against all three of the pathogens. We also tested these compounds against normal human cells and there were no observable effects. Given that new antibiotics often negatively impact normal flora of the patient, we also screened the entire set of new compounds on several known normal flora bacteria and observed no change in growth at the highest concentration tested. Taken together, this work shows that several of these compounds are selective for three different human pathogens; and demonstrate potential new leads for drug discovery against these three significant human and animal diseases.

Technical Abstract: Although chemotherapy is the sole option for the treatment of sleeping sickness, over the past forty years no new chemical agent has been registered to treat this disease; as such only four long discovered drugs are currently in clinics to treat the foregoing disease. These drugs have as major limitations; poor oral bioavailability and numerous serious toxic side effects, which necessitate the search for new drugs. Benzoxaborole is a new scaffold that has garnered considerable appraisal as an anti-parasitic agent that displays good pharmacokinetic properties and low toxicities. In this work, a set of novel benzoxaborole-cinnamic acid hybrids were synthesised and screened against T.b. brucei and HeLa cell lines for trypanocidal activity and cytotoxicity, respectively. Compound 3j emerged as a new hit with in vitro IC50 value of 0.052µM and a selectivity index '2500. These compounds were also cross-screened against several other human pathogens, including Mycobacterium tuberculosis, wherein some moderate activities were observed. Interestingly, these compounds also demonstrated moderate activity against the human protozoal pathogen Trichomonas vaginalis, with no observed effect on common microbiome bacterial species. The cross-species inhibitory activity presents the possibility of these compounds serving as broad-spectrum antibiotics for these prevalent three human pathogens.