Design, synthesis, in vitro and in vivo trypanosomaticidal efficacy of novel 5-nitroindolylazines

Leishmaniasis and trypanosomiasis rank among lethal vector-borne parasitic diseases that are endemic in tropical and sub-tropical countries. There are currently no preventive vaccines against them, and once diagnosed, a handful of less effective drugs clinically accessible are the only therapeutic options offered to treat these ailments. And although curable, the eradication and elimination of these diseases are hampered by the emergence of multidrug-resistant strains of the causal pathogens. Hence, there is accrued necessity for the development of new, effective, and affordable drugs. In recent decades, several molecular scaffolds, including nitroaromatics, endoperoxides, etc., have been attempted as building blocks to generate new effective clinical antitrypanosomatid agents with low toxicity so far to no avail. In this regard, a series of nitroindolylazine derivatives was synthesised in a three-step process involving nucleophilic substitution (S_N), hydrazination and Schiff base condensation reactions, and was evaluated against various Leishmania and Trypanosoma species and strains. Several promising hits portraying leishmanicidal and trypanocidal with in vitro submicromolar activities, and devoid of toxicity on mammalian cells were uncovered. Among these, nitrofurylazine 11 (Tc IC₅₀: 0.08 ± 0.03 μM) and nitrothienylazine 13 (Tc IC₅₀: 0.09 ± 0.01 μM) were evaluated in vivo against Trypanosoma congolense, the causative agent of nagana, which is livestock most virulent trypanosome species in mice-infected preliminary study. However, only partial efficacy was observed as all mice succumbed due to high parasitemia within 13 days post-infection during the treatment. The translational potential of antileishmanial and antichagasic hits, as well as further identification of their molecular targets, will be assessed in future research.