Search

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 IC 50 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 IC 50 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. [Display omitted] • (1-Benzyl-4-triazolyl)-indole-2-carboxamide show interesting antiparasitic activity. • Compounds' concentrations of 1.94–7.63 μM inhibited growth of T. gondii & C. parvum. • The best hits displayed in vivo efficacy comparable to the standard drug atovaquone. • Those compounds show good potential for further development as antiparasitic agents. [ABSTRACT FROM AUTHOR]

Objectives include (1) To create an opportunity for students enrolled in pharmacy programs to enhance their presentation skills by delivering research podium presentations at a regional conference; (2) To probe students' experience about podium presentations at the inaugural American Association for the Advancement of Science Pacific Division (AAAS PD) – American Association of Colleges of Pharmacy Students' Symposium; and (3) To introduce student pharmacists to science-oriented research. The student presenters were asked to anonymously answer 15 questions before and after the symposium. Question topics included factual information about students' background and favorability perceptions about symposia. Scores were compared between pharmacy students and non-pharmacy students, and favorability ratings were compared before and after the symposium. Thirteen students delivered their podium presentations at the symposium entitled "Pharmaceutical Research and Development: From Bench to Patient-Centered Care" that was held in Pomona, California at the 99th Annual Meeting of the AAAS PD in 2018. Pharmacy and non-pharmacy students provided similar responses on favorability perceptions. Post-symposium perceptions were more favorable towards symposia compared to pre-symposium scores. Favorability scores revealed a positive perception of the event and what it offered in terms of scientific benefits, networking opportunities, and enhancing soft skills. Participating students had the chance to (1) prepare and independently deliver a podium presentation on pharmacy-related research topics at a regional meeting; (2) network and learn from each other and professionals in the audience about pharmacy research; and (3) practice soft skills such as communication, time-management, teamwork, scientific writing, and presentation skills. [ABSTRACT FROM AUTHOR]

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 IC 50 concentration (1.21 μM) that was nearly 53-fold lower than its cytotoxicity IC 50 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 IC 50 concentration (32.24 μM) that was 14-fold lower than its cytotoxicity IC 50 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. Image 1 • A focused library of acyl/diacyl ureas and acyl carbamates was efficiently prepared. • Select compounds inhibited the in vitro growth of T. gondii and C. parvum parasites. • The diacyl urea compound JS-1-09 showed good activity against T. gondii parasites. • The identified hit shows potential for further development as novel antiprotozoal agent. [ABSTRACT FROM AUTHOR]

Abstract: The enoyl acyl-carrier protein reductase (ENR) enzyme is harbored within the apicoplast of apicomplexan parasites providing a significant challenge for drug delivery, which may be overcome through the addition of transductive peptides, which facilitates crossing the apicoplast membranes. The binding site of triclosan, a potent ENR inhibitor, is occluded from the solvent making the attachment of these linkers challenging. Herein, we have produced 3 new triclosan analogs with bulky A- and B-ring motifs, which protrude into the solvent allowing for the future attachment of molecular transporters for delivery. [Copyright &y& Elsevier]

Abstract: Insertion of allenyl carbenoids (3-tosyloxy-1-lithioalk-1-ynes) into organozirconium complexes gave allenyl-zirconocenes via a 1,2-zirconate rearrangement. Trapping of the allenyl-zirconium species with aldehydes and ketones gave, after hydrolysis, a series of homopropargyl alcohols. Enantioenriched products were prepared by insertion of the lithium carbenoid derived from (S)-but-3-yn-2-yl 4-toluenesulfonate into alkyl- and alkenyl-chlorozirconocenes. [Copyright &y& Elsevier]