Abstract
Purpose: To synthesize a series of novel thiazolo pyrimidine derivatives and evaluate them in vitro and in vivo for their safety and anti-leishmanial activity using BALB/c mice. Methods: Substituted pyrazolopyrimidine and pyrazolopyrazole were synthesized by reacting amino group of 2-amino-4-cyano-pyrazol]naphthalino[1,2-d]thiazole with a variety of formamide or hydrazine hydrate. The synthesized compounds were characterized by nuclear magnetic resonance spectroscopy (1H-NMR) and mass spectroscopy (MS). The purity of the compounds was determined by elemental analysis. Safety and anti-leishmanial activity of the compounds were determined in vitro by i) viability assessment of leishmania-infected macrophages, relative abundance of IL-12p40 mRNA gene expression and levels of IL10 /IL-12 determination in supernatants of cultured macrophages treated with 2.5 and 10 μM of the compounds, using microscope cell counting, reverse transcriptase polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA), respectively. ii) cytotoxicity of the compounds evaluated by determination the safety index as IC 50 of the compound in macrophages/IC 50 of the compound in amastigotes. iii) bioassay at 16 weeks post-infection of mice treated with the reference drug, the tested compound alone and both the compound with IL-12. Disease progression and footpad thickness were evaluated regularly during treatment. Results: Compound 4 emerged as the most active anti-protozoal compound of the series against Leishmania viability (activity 60 %) compared with the reference drug (activity 65 %). When it was combined with IL-12, the activity reached 90 %. Conclusion: Compound 4 can serve as a lead molecule for further development to a clinically useful novel class of agents. Keywords: Thiazolopyrimidine, Synthesis, Leishmaniasis, Mice, Immunotherapy
Highlights
Leishmaniasis, caused by the protozoan parasite of the genus Leishmania, affects over 12 million individuals worldwide, 1.5 – 2 million of whom develop symptomatic disease every year [1]
We have reported the synthesis of substituted pyrazolopyrimidine 3 and pyrazolopyrazole 4 by using 1-(naphtho[1,2d]thiazol-2-yl)hydrazine 1 as starting material
The anti-leishmanial activity of the synthetic compounds (0 - 25 μM) was evaluated in terms of the intracellular parasite load, wherein the infection rate of Leishmania infected macrophages was normalized to 100 %; with the addition of the tested compound, a dose dependent reduction in parasitic load was evident, the IC50 being 2.5 μM (Fig. 1)
Summary
Leishmaniasis, caused by the protozoan parasite of the genus Leishmania, affects over 12 million individuals worldwide, 1.5 – 2 million of whom develop symptomatic disease every year [1]. The parasite is spread by the sand fly vector and causes a spectrum of diseases depending on the parasite species and the host immune status. Clinical manifestations of the disease range from self-limiting cutaneous Leishmaniasis, disfiguring muco-cutaneous Leishmaniasis, to fatal visceral leishmaiasis. These treatments are laborious and expensive, cause severe side effects and emerging drug resistance has been reported [2]. An alternative effective treatment regime would be desirable
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