Synthesis of hydrazinyl-thiazole ester derivatives, in vitro trypanocidal and leishmanicidal activities.

Aim: To synthesize novel more potent trypanocidal and leishmanicidal agents. Methods: Hantzsch's synthetic strategy was used to synthesize 1,3-thiazole-4-carboxylates and their N-benzylated derivatives. Results: 28 new thiazole-carboxylates and their N-benzylated derivatives were established to test their trypanocidal and leishmanicidal activities. From both series, compounds 3b, 4f, 4g, 4j and 4n exhibited a better or comparable trypanocidal profile to benznidazole. Among all tested compounds, 4n was found to be the most potent and was better than benznidazole. Conclusion: Further variation of substituents around 1,3-thiazole-4-carboxylates and or hydrazinyl moiety may assist in establishing better and more potent trypanocidal and leishmanicidal agents.

Chagas disease and leishmaniasis are neglected tropical diseases. Herein, 28 1,3-thiazoles have been synthesized from thiosemicarbazones in a rapid, efficient and cost-effective manner. In vitro assays were performed against intracellular amastigotes of Trypanosoma cruzi (T. cruzi) and promastigotes and intracellular amastigote forms of Leishmania infantum (L. infantum) and Leishmania amazonensis (L. amazonensis). Some of the 1,3-thiazole-4-carboxylates inhibited the amastigote form of T. cruzi without affecting macrophage viability, compound 4n being the most potent and better than benznidazole. Our synthesized compounds exhibited promising activity against T. cruzi, thus broadening options for scaffold and lead compound optimization. Concerning the leishmanicidal activity, compound 4g was the best prototype in terms of potency and selectivity. Compounds 4g and 3m showed moderate selectivity and potency against intracellular amastigotes of L. amazonensis and L. infantum, respectively.

Characterizing drug-metabolizing enzymes and transporters that areCAR-target genes in mouse intestine

Intestine is responsible for the biotransformation of many orally-exposed chemicals. The constitutive androstane receptor (CAR/Nr1i3) is known to up-regulate many genes encoding drug-metabolizing enzymes and transporters (drug-processing genes/DPGs) in liver, but less is known regarding its effect in intestine. Sixty-day-old wild-type andmice were administered the CAR-ligand TCPOBOP or vehicle once daily for 4 days. In wild-type mice,mRNA was down-regulated by TCPOBOP in liver and duodenum.mice had altered basal intestinal expression of many DPGs in a section-specific manner. Consistent with the liver data (Aleksunes and Klaassen, 2012), TCPOBOP up-regulated many DPGs (, and) in specific sections of small intestine in a CAR-dependent manner. However, the mRNAs ofandwere previously known to be up-regulated by TCPOBOP in liver but were not altered in intestine. Interestingly, many known CAR-target genes were highest expressed in colon where CAR is minimally expressed, suggesting that additional regulators are involved in regulating their expression. In conclusion, CAR regulates the basal expression of many DPGs in intestine, and although many hepatic CAR-targeted DPGs wereCAR-targets in intestine, pharmacological activation of CAR in liver and intestine are not identical.