Activity of (1-benzyl-4-triazolyl)-indole-2-carboxamides against Toxoplasma gondii and Cryptosporidium parvum.

Parasitic diseases such as toxoplasmosis and cryptosporidiosis remain serious global health challenges, not only to humans but also to domestic animals and wildlife. With only limited treatment options available, Toxoplasma gondii and Cryptosporidium parvum (the causative agents of toxoplasmosis and cryptosporidiosis, respectively) constitute a substantial health threat especially to young children and immunocompromised individuals. Herein, we report the synthesis and biological evaluation of a series of novel (1-benzyl-4-triazolyl)-indole-2-carboxamides and related compounds that show efficacy against T. gondii and C. parvum. Closely related analogs 7c (JS-2-30) and 7e (JS-2-44) showed low micromolar activity with IC50 indices ranging between 2.95 µM and 7.63 µM against both T. gondii and C. parvum, whereas the compound representing (1-adamantyl)-4-phenyl-triazole, 11b (JS-2-41), showed very good activity with an IC50 of 1.94 µM, and good selectivity against T. gondii in vitro. Importantly, compounds JS-2-41 and JS-2-44 showed appreciable in vivo efficacy in decreasing the number of T. gondii cysts in the brains of Brown Norway rats. Together, these results indicate that (1-benzyl-4-triazolyl)-indole-2-carboxamides and (1-adamantyl)-4-phenyl-triazoles are potential hits for medicinal chemistry explorations in search for novel antiparasitic agents for effective treatment of cryptosporidiosis and toxoplasmosis.

Novel acyl carbamates and acyl / diacyl ureas show in vitro efficacy against Toxoplasma gondii and Cryptosporidium parvum.

Toxoplasma gondii and Cryptosporidium parvum are protozoan parasites that are highly prevalent and opportunistically infect humans worldwide, but for which completely effective and safe medications are lacking. Herein, we synthesized a series of novel small molecules bearing the diacyl urea scaffold and related structures, and screened them for in vitro cytotoxicity and antiparasitic activity against T. gondii and C. parvum. We identified one compound (GMG-1-09), and four compounds (JS-1-09, JS-2-20, JS-2-35 and JS-2-49) with efficacy against C. parvum and T. gondii, respectively, at low micromolar concentrations and showed appreciable selectivity in human host cells. Among the four compounds with efficacy against T. gondii, JS-1-09 representing the diacyl urea scaffold was the most effective, with an anti-Toxoplasma IC50 concentration (1.21 µM) that was nearly 53-fold lower than its cytotoxicity IC50 concentration, indicating that this compound has a good selectivity index. The other three compounds (JS-2-20, JS-2-35 and JS-2-49) were structurally more divergent from JS-1-09 as they represent the acyl urea and acyl carbamate scaffold. This appeared to correlate with their anti-Toxoplasma activity, suggesting that these compounds' potency can likely be enhanced by selective structural modifications. One compound, GMG-1-09 representing acyl carbamate scaffold, depicted in vitro efficacy against C. parvum with an IC50 concentration (32.24 µM) that was 14-fold lower than its cytotoxicity IC50 concentration in a human intestinal cell line. Together, our studies unveil a series of novel synthetic acyl/diacyl urea and acyl carbamate scaffold-based small molecule compounds with micromolar activity against T. gondii and C. parvum that can be explored further for the development of the much-needed novel anti-protozoal drugs.

Highly-efficient charge separation and polaron delocalization in polymer-fullerene bulk-heterojunctions: a comparative multi-frequency EPR and DFT study.

The ongoing depletion of fossil fuels has led to an intensive search for additional renewable energy sources. Solar-based technologies could provide sufficient energy to satisfy the global economic demands in the near future. Photovoltaic (PV) cells are the most promising man-made devices for direct solar energy utilization. Understanding the charge separation and charge transport in PV materials at a molecular level is crucial for improving the efficiency of the solar cells. Here, we use light-induced EPR spectroscopy combined with DFT calculations to study the electronic structure of charge separated states in blends of polymers (P3HT, PCDTBT, and PTB7) and fullerene derivatives (C60-PCBM and C70-PCBM). Solar cells made with the same composites as active layers show power conversion efficiencies of 3.3% (P3HT), 6.1% (PCDTBT), and 7.3% (PTB7), respectively. Upon illumination of these composites, two paramagnetic species are formed due to photo-induced electron transfer between the conjugated polymer and the fullerene. They are the positive, P(+), and negative, P(-), polarons on the polymer backbone and fullerene cage, respectively, and correspond to radical cations and radical anions. Using the high spectral resolution of high-frequency EPR (130 GHz), the EPR spectra of these species were resolved and principal components of the g-tensors were assigned. Light-induced pulsed ENDOR spectroscopy allowed the determination of (1)H hyperfine coupling constants of photogenerated positive and negative polarons. The experimental results obtained for the different polymer-fullerene composites have been compared with DFT calculations, revealing that in all three systems the positive polaron is distributed over distances of 40-60 Å on the polymer chain. This corresponds to about 15 thiophene units for P3HT, approximately three units for PCDTBT, and about three to four units for PTB7. No spin density delocalization between neighboring fullerene molecules was detected by EPR. Strong delocalization of the positive polaron on the polymer donor is an important reason for the efficient charge separation in bulk heterojunction systems as it minimizes the wasteful process of charge recombination. The combination of advanced EPR spectroscopy and DFT is a powerful approach for investigation of light-induced charge dynamics in organic photovoltaic materials.