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Background: Approximately 89% of the US population lives within five miles of a community pharmacy, which provides a network of geographically distributed recruitment nodes for testing and surveillance of infection and disease., Objectives: Establish feasibility of Pharmacy-based Research Opportunities To Enhance Community Testing and Surveillance in the context of SARS-CoV-2 infection in a community pharmacy setting with University of Kentucky serving as the coordinating center and research hub for sample analysis., Methods: Two community pharmacies in Kentucky served as community-based recruitment sites to assess SARS-CoV-2 exposure through longitudinal (5 visits over 56 days) collection of nasal swabs and blood samples from subjects., Results: Fifty subjects were recruited between May 2022 and December 2023 for longitudinal sample collection. Three phases of recruitment were investigated by first establishing standard operating procedures in an urban pharmacy, then expanding recruitment at a second pharmacy in a rural setting, and finally increasing recruitment at the urban pharmacy. During the first phase of recruitment, 12 participants were recruited. Of these participants, two never scheduled a visit after the initial screening. The median time for study completion from first to last visit within this phase was 59 days (interquartile range: 56-68 days). During the second phase of recruitment, eight of nine participants completed all five visits. The median time to complete all visits was 105 days (interquartile range: 98-112 days). During the ongoing third phase, 29 subjects were recruited, and 19 participants completed all required visits and the remainder continue to schedule follow-up appointments., Conclusion: Community pharmacies have a significant role in promoting public health. The geographic distribution of community pharmacies makes them appealing locations for recruitment of outpatient cohorts for local surveillance of infections and chronic inflammatory conditions with opportunities for broad implementation of this project for clinical trials in underserved communities., Competing Interests: Disclosure Vincent J. Venditto is supported by grants from the National Institutes of Health (R01HL152081, P20GM130456). The authors declare no other relevant conflicts of interest or financial relationships., (Copyright © 2024 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

A series of n-alkyl/aryl esters were synthesized and their in vitro antiplasmodial activity was measured alongside that of previously synthesized aminoethylethers of artemisinin ozonides against various strains of Plasmodium falciparum. The cytotoxicity against human cell lines was also assessed. The esters were synthesized in a one-step reaction by derivatization on carbon C-10 of dihydroartemisinin. Both classes were active against both the 3D7 and K1 strains of P. falciparum, with all compounds being significantly more potent than artemether against both strains. The majority of compounds possessed potency either comparable or more than artesunate with a high degree of selectivity towards the parasitic cells. The 10α-n-propyl 11 and 10α-benzyl 18 esters were the most potent of all synthesized ozonides, possessing a moderate (~3-fold) and significant (22- and 12-fold, respectively) potency increases against the 3D7 and K1 strains, respectively, in comparison with artesunate., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Malaria, a devastating infectious disease caused by Plasmodium spp., leads to roughly 655,000 deaths per year, mostly of African children. To compound the problem, drug resistance has emerged to all classical antimalarials and may be emerging for artemisinin-based combination therapies. To address the need for new antimalarials with novel mechanisms, several groups carried out phenotypic screening campaigns to identify compounds inhibiting growth of the blood stages of Plasmodium falciparum. In this review, we describe the characterization of these compounds, explore currently ongoing strategies to develop lead molecules, and endorse the concept of a "malaria box" of publicly accessible active compounds., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The most common methods for discovery of chemical compounds capable of manipulating biological function involves some form of screening. The success of such screens is highly dependent on the chemical materials - commonly referred to as libraries - that are assayed. Classic methods for the design of screening libraries have depended on knowledge of target structure and relevant pharmacophores for target focus, and on simple count-based measures to assess other properties. The recent proliferation of two novel screening paradigms, structure-based screening and high-content screening, prompts a profound rethink about the ideal composition of small-molecule screening libraries. We suggest that currently utilized libraries are not optimal for addressing new targets by high-throughput screening, or complex phenotypes by high-content screening.

We have synthesized a series of phenothiazine derivatives, which were used to test the structure-activity relationship of binding to HIV-1 TAR RNA. Variations from our initial compound, 2-acetylphenothiazine, focused on two moieties: ring substitutions and n-alkyl substitutions. Binding characteristics were ascertained via NMR, principally by saturation transfer difference spectra of the ligand and imino proton resonance shifts of the RNA. Both ring and alkyl substitutions manifested NMR changes upon binding. In general, the active site, while somewhat flexible, has regions that can be capitalized for increased binding through van der Waals interactions and others that can be optimized for solubility in subsequent stages of development. However, binding can be nontrivially enhanced several-fold through optimization of van der Waals and hydrophilic sites of the scaffold.

Ligand-dependent nuclear hormone receptor (NR) signaling requires direct interaction between NR and the steroid receptor coactivators (SRC). Herein we utilize a library of SRC2 peptidomimetics to select for specific inhibitors of the interaction of SRC2 with the two estrogen receptor (ER) isoforms, ERalpha and ERbeta, in the presence of three different ligands: 17beta-estradiol, diethylstilbesterol, and genistein. The pattern of inhibitor selectivity for each ER isoform varied depending upon which ligand was present, thus demonstrating that the ligands exert unique allosteric effects upon the surface of the SRC binding pocket. Several of the lead compounds are highly (>100-fold) selective for blocking the binding of SRC2 to ERalpha, in preference to ERbeta, in the presence of one ligand and therefore may prove useful for decoupling ERbeta signaling from ERalpha signaling.

Background: Taxol is a natural product produced by the Pacific yew, Taxus brevifolia, that has emerged as a prominent chemotherapeutic agent for the treatment of solid tumors. It binds to microtubules, stabilizing them and arresting cells in mitosis. Taxol has been produced synthetically and a wealth of structure-activity data has recently emerged. To data, however, no single conformational model exists for the interpretation of these data. Studies of taxol and its analogs in organic solvents showed two distinct conformations, one in which the 3'-benzamido group and the 2-benzoyl group are in close proximity, and another in which the 2-benzoyl group is instead close to the 3'-phenyl group. We decided to use a derivative of taxol that has improved water-solubility to determine the structure of taxol in water., Results: We have synthesized and characterized a stable water-soluble derivative of taxol that binds to microtubules and has a cytotoxicity profile very similar to that of taxol. 1D and 2D 1H NMR experiments with this bioactive compound in D2O indicate the presence of one conformer with a well-defined structure. In this structure, the 2-benzoyl group is clustered with the 3'-phenyl group., Conclusion: The determination of the conformation of taxol in water may allow quantitative three-dimensional interpretation of the structure-activity data obtained for taxol, and hence enable the design of novel taxol mimics.