In Vitro and In Vivo Trypanocidal Efficacy of Nitrofuryl- and Nitrothienylazines

Abstract

African trypanosomiasis is a vector-borne disease of animals and humans in the tsetse fly belt of Africa. Trypanosoma congolense ("nagana") is the most pathogenic trypanosome in livestock and causes high morbidity and mortality rates among cattle. In the absence of effective preventative vaccines, the management of trypanosomiasis relies on chemoprophylaxis and/or -therapy. However, the trypanocides in clinical use exhibit poor oral bioavailability and toxicity, and therapeutic failures occur because of resistant strains. Because nitrofurantoin displayed, in addition to its clinical use, promising antiparasitic activity, the current study was conducted to evaluate the in vitro trypanocidal activity and preliminary in vivo treatment efficacy of previously synthesized nitrofuranylazines. The trypanocidal activity of these nitrofuran derivatives varied among the evaluated trypanosome species; however, T. congolense strain IL3000 was more susceptible than other animal and human trypanosomes. The nitrofurylazines 4a (IC 50 0.04 μM; SI > 7761) and 7a (IC 50 0.03 μM; SI > 9542) as well as the nitrothienylazine 8b (IC 50 0.04 μM; SI 232), with nanomolar IC 50 values, were revealed as early antitrypanosomal leads. Although these derivatives showed strong trypanocidal activity in vitro, no in vivo treatment efficacy was observed in T. congolense IL3000 infected mice after both oral and intraperitoneal administration in a preliminary study. This was attributed to the poor solubility of the test compounds in the in vivo testing media. Indeed, a challenge in drug discovery is finding a balance between the physicochemical properties of a drug candidate, particularly lipophilicity and water solubility, and maintaining adequate potency to provide an effective dose. Hence, future chemical modifications may be required to generate lead-like to lead-like nitrofuranylazines that possess optimal physicochemical and pharmacokinetic properties while retaining in vitro and, ultimately, in vivo trypanocidal efficacy.

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“…Egan filter (Pharmacia filter) anticipates that drug absorption depends on processes involved in the membrane permeability of the small molecule. These models symbolize molecules as a drug if they have WLOGP ≤5.88 and TPSA ≤ 131.6 respectively 8 . Muegge filter (Bayer filter) is a selfreliant Pharmacophore point filter that segregates drug-like and non-drug-like molecules.…”

“…ADME (absorption, distribution, metabolism, and excretion) studies play a vital role in drug discovery and development with the support of technology, software like SwissADME allows the prediction and compilation of ADME parameters i.e., Physiological properties, Lipophilicity, Water solubility, Pharmacokinetics, Drug likeness, Medicinal chemistry. Selective coumarins present in A.M. like umbelliferon, scopoletin, scoparone, xanthotoxol, marmesin, psoralen, imperatorin (also known as Marmelosin or marmelide), alloimperatorin, and marmin [8][9][10][11][12][13] were taken for in-silico ADME screening using SwissADME software.…”