Novel immunomodulatory function of 1,3,4-thiadiazole derivatives with leishmanicidal activity

Previously, some nitroheteroaryl-1,3,4-thiadiazole derivatives were identified to have potent activity against Leishmania sp. The present aim was to complete the in vitro analysis, thereby investigating the in vivo efficiency of the analogues 15a, 21a and 21b against infected BALB/c mice. Following parasite inoculation and intraperitoneal drug administration (5 and 20 mg/kg/day) for 5 days, the course and size of cutaneous lesions, histopathology of the liver, parasite loads in the spleen through limiting dilution assay as well as spleen cell activation assays through cytokine secretion profiles were studied in BALB/c mice, over a period of 23 and 30 days post-drug injections. The analogues significantly decreased lesion size and progression of infection in the liver and spleen, and were associated with granuloma formation, which correlates with disease regression in the liver of murine hosts. Moreover, the analogues had immunomodulatory effects, stimulating interferon- expression and suppressing interleukin-10 and interleukin-5 production, favouring type-1 immune responses and resolution of the parasitic infection. Our results highlight marked differences between the responses of key anatomical organs to the thiadiazole derivatives in comparison with the current antileishmanial drug, meglumine antimoniate. The in vivo observations provide further evidence on the efficiency of the compounds for Leishmania treatment. The immunomodulatory function plays an essential role in enhancing cell-mediated immunity for complete clearance of the pathogen.