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The leishmaniasis are a group of vector-borne diseases caused by a protozoan parasite from the genus Leishmania. In this study, a series of thiazolopyrimidine derivatives were designed and synthesized as novel antileishmanial agents with Lm PTR1 inhibitory activity. The final compounds were evaluated for their in vitro antipromastigote activity, Lm PTR1 and h DHFR enzyme inhibitory activities, and cytotoxicity on RAW264.7 and L929 cell lines. Based on the bioactivity results, three compounds, namely L24f , L24h and L25c , were selected for evaluation of their in vivo efficacy on CL and VL models in BALB/c mice. Among them, two promising compounds, L24h and L25c, showed in vitr o antipromastigote activity against L. tropica with the IC 50 values of 0.04 μg/ml and 6.68 μg/ml; against L. infantum with the IC 50 values of 0.042 μg/ml and 6.77 μg/ml, respectively. Moreover, the title compounds were found to have low in vitro cytotoxicity on L929 and RAW264.7 cell lines with the IC 50 14.08 μg/ml and 21.03 μg/ml, and IC 50 15.02 μg/ml and 8.75 μg/ml, respectively. Lm PTR1 enzyme inhibitory activity of these compounds was determined as 257.40 μg/ml and 59.12 μg/ml and their selectivity index (SI) over h DHFR was reported as 42.62 and 7.02, respectively. In vivo studies presented that L24h and L25c have a significant antileishmanial activity against footpad lesion development of CL and at weight measurement of VL group in comparison to the reference compound, Glucantime®. Also, docking studies were carried out with selected compounds and other potential Leishmania targets to detect the putative targets of the title compounds. Taken together, all these findings provide an important novel lead structure for the antileishmanial drug development. [Display omitted] • A series of thiazolopyrimidine derivatives were synthesized as novel antileishmanials. • L24f , L24h and L25c showed in vitro antipromastigote activity and low cytotoxicity. • L24f , L24h and L25c showed moderate Lm PTR1 inhibition and h DHFR selectivity. • L24h and L25c have shown in vivo activity on CL and VL models of BALB/c mice. [ABSTRACT FROM AUTHOR]

Abstract: Over a period of ten years, a series of 694 Leishmania strains from Tunisian leishmaniasis foci were isolated and identified by isoenzymatic analysis. Strains were obtained from human cutaneous and visceral leishmaniasis in immunocompetent subjects, visceral leishmaniasis in imunocompromised individuals and from dogs with visceral leishmaniasis. Two classically dermotropic species, Leishmania (L.) major and Leishmania killicki were found. L. major with the single zymodeme MON-25 was the most isolated in cutaneous leishmaniasis foci of the Centre and South of Tunisia with a recent northern extension. L. killicki zymodeme MON-8 was sporadically found both in its classical microfocus of Tataouine in southeastern Tunisia as well as in some new foci in Southwestern, Central and Northern Tunisia. Leishmania infantum with its three zymodemes MON-1, MON-24 and MON-80 was isolated from both visceral and cutaneous human cases. The majority of L. infantum strains were found in the Northern part of the country; however, some strains were reported for the first time in the Southern part. L. infantum MON-1 was the only zymodeme isolated from canine leishmaniasis. [Copyright &y& Elsevier]