A review of phenformin, metformin, and imeglimin.

Diabetes mellitus is a serious metabolic disorder affecting millions of people worldwide. Phenformin and metformin are biguanide antidiabetic agents that are conveniently synthesized in a single-step chemical reaction. Phenformin was once used to lower blood glucose levels, but later withdrawn from the market in several countries because it was frequently associated with lactic acidosis. Metformin is still a widely prescribed medication for the treatment of type 2 diabetes despite the introduction of several newer antidiabetic agents. Metformin is administered orally and has desirable pharmacokinetics. Incidence of metformin-induced lactic acidosis is serious but very rare. Imeglimin, a novel molecule being investigated by Poxel and Sumitomo Dainippon Pharma in Japan, is currently in clinical trials for the treatment of type 2 diabetes. Unlike metformin, imeglimin is a cyclic molecule containing a triazine ring. However, like metformin, imeglimin is also a basic small molecule. Imeglimin is synthesized from metformin as a precursor via a single step chemical reaction. Recent mechanism of action studies suggests that imeglimin improves mitochondria function, when given in combination with metformin it helps achieve better glycemic control in patients with type 2 diabetes. We herein describe and compare the current status, synthesis, physicochemical properties, pharmacokinetic parameters, mechanism of action, and preclinical/clinical studies of metformin and imeglimin.

Spermine and Spermidine Alter Gene Expression and Antigenic Profile of Borrelia burgdorferi.

Borrelia burgdorferi, the agent of Lyme disease, responds to numerous host-derived signals to alter adaptive capabilities during its enzootic cycle in an arthropod vector and mammalian host. Molecular mechanisms that enable B. burgdorferi to detect, channel, and respond to these signals have become an intense area of study for developing strategies to limit transmission/infection. Bioinformatic analysis of the borrelial genome revealed the presence of polyamine transport components (PotA, PotB, PotC, and PotD), while homologs for polyamine biosynthesis were conspicuously absent. Although potABCD is cotranscribed, the level of PotA was elevated under in vitro growth conditions mimicking unfed ticks compared to the level in fed ticks, while the levels of PotD were similar under the aforementioned conditions in B. burgdorferi Among several polyamines and polyamine precursors, supplementation of spermine or spermidine in the borrelial growth medium induced synthesis of major regulators of gene expression in B. burgdorferi, such as RpoS and BosR, with a concomitant increase in proteins that contribute to colonization and survival of B. burgdorferi in the mammalian host. Short transcripts of rpoS were elevated in response to spermidine, which was correlated with increased protein levels of RpoS. Transcriptional analysis of rpoZ and B. burgdorferirel (relBbu ; bb0198) in the presence of spermidine revealed the interplay of multiple regulatory factors in B. burgdorferi gene expression. The effect of spermidine on the levels of select borrelial proteins was also influenced by serum factors. These studies suggest that multiple host-derived signals/nutrients and their transport systems contribute to B. burgdorferi adaptation during the vector and vertebrate host phases of infection.

Synthesis and Evaluation of Thiazolidine Amide and N-Thiazolyl Amide Fluoroquinolone Derivatives.

In an effort to develop new fluoroquinolones, we synthesized eight compounds and tested them against a panel of bacteria. The design of these compounds was guided by the introduction of the isothiazoloquinolone motif. The three most active compounds in this series, 8-10, demonstrated good antibacterial activity against methicillin-sensitive Staphylococcus aureus and healthcare-acquired methicillin-resistant Staphylococcus aureus (MIC 0.62-6.3 µg/mL). Further, when these three active compounds were tested for their inhibitory effects on bacterial enzymes, compound 9 was the most effective agent exhibiting IC50 values of 33.9 and 116.5 µM in the S. aureus deoxyribonucleic acid (DNA) gyrase supercoiling and topoisomerase IV decatenation assays, respectively.

The "first-generation effect" on perceptions and academic performance of pharmacy students.

INTRODUCTION: The "first-generation effect" refers to familial educational attainment's role in first-generation student academic success. It often implies low academic achievements at associate and bachelor degree levels. Would this be true at the doctor of pharmacy (PharmD) level? This study assessed perceptions and first-professional (P1) year student academic performance of first-generation vs. non-first-generation PharmD cohorts at the Feik School of Pharmacy. METHODS: Perceptions (academic and personal support) were assessed via a 49-question survey at the start of the second- and third-professional years. Academic performance was assessed via measures of academic success (course grades, grade point average, supplemental instruction enrollments, and academic infractions) in P1 year. Statistical t-tests and F-tests were used to analyze differences in perceptions and academic performance for the two cohorts. RESULTS: From 132 eligible students, 128 completed the survey (97% response rate) and 58 (45%) were first-generation students. First-generation students had a lower perception of their academic success, and they perceived finances as one of their greatest barriers (86% vs. 64%). Fifteen P1 courses were reviewed for academic performance, and first generations had lower final course grades in only two courses (Anatomy and Physiology 1; Medical Microbiology and Immunology). For measures of academic success, no significant differences were noted. CONCLUSIONS: Overall, this study suggested that first-generation status may not be a hindrance to academic performance at the PharmD level, but that financial perceptions and a lower self-perception of academic success seem to be major barriers for first-generation PharmD students.

Evaluation of analogs of reutericyclin as prospective candidates for treatment of staphylococcal skin infections.

The potential for reutericyclin derivatives to be used as topical antibiotics to treat staphylococcal skin infections was investigated. All reutericyclins inhibited the growth of clinical isolates of drug-resistant Staphylococcus aureus. Unlike the standard topical agent mupirocin, most reutericyclin derivatives eradicated staphylococcal biofilms. Moreover, two compounds formulated in hydrophilic petrolatum (10%, wt/wt) were efficacious in treating S. aureus superficial skin infections in mice. These data exemplify the prospect of developing reutericyclins as new topical antibiotics.

N-substituted 3-acetyltetramic acid derivatives as antibacterial agents.

In order to expand the structure-activity relationship of tetramic acid molecules with structural similarity to the antibiotic reutericyclin, 22 compounds were synthesized and tested against a panel of clinically relevant bacteria. Key structural changes on the tetramic acid core affected antibacterial activity. Various compounds in the N-alkyl 3-acetyltetramic acid series exhibited good activity against Gram-positive bacterial pathogens including Bacillus anthracis, Propionibacterium acnes, Enterococcus faecalis, and both Methicillin-sensitive and -resistant Staphylococcus aureus.

Design, synthesis, and evaluation of novel ethambutol analogues.

Ethambutol is one of the front-line agents recommended by the World Health Organization for the treatment of tuberculosis. In an effort to develop more potent therapies to treat tuberculosis, novel unsymmetrical ethambutol analogues were successfully synthesized by a new route utilizing novel building blocks synthesized using Ellman's sulfinyl chemistry. The resulting analogues were tested for anti-tuberculosis activity yielding compounds with comparable anti-tuberculosis activity to ethambutol and increased lipophilicity that may instill better tissue penetration and serum half-life.

Alzheimer's Drug Discovery Maze: A Snap View of the Past Decade's Diverse Pharmacological Targets for the Disorder.

The discovery of disease modifying anti-Alzheimer's molecules continues to be dared by: disease target multiplicity, downstream neurodegenerative biochemistry complexities, and genotype implications. A confluence of the above ingredients has contributed to a pipeline of creative molecules that regrettably underperform in clinical trials. Thus far, only five palliative pharmacotherapeutic agents, that is, four acetylcholine potentiating agents and an N-methyl-D-aspartate (NMDA) antagonist are clinically available. In this review we collectively describe the currently suggested targetable pathways for designing anti-Alzheimer's agents (palliative and/or disease modifying). We are prompted to contribute in this manner out of a desire to simplify and consolidate, to a certain extent, the divergent target literature on Alzheimer's drug discovery. We herein provide a summary update and perspective on realized and potentially druggable pharmacological targets for this CNS disorder. This article covers mostly the 2005-2015 medicinal chemistry/pharmacological/biological literature space on the subject.

Synthesis and evaluation of cyclic secondary amine substituted phenyl and benzyl nitrofuranyl amides as novel antituberculosis agents.

In an ongoing effort to develop new and potent antituberculosis agents, a second-generation series of nitrofuranyl amides was synthesized on the basis of the lead compound 5-nitrofuran-2-carboxylic acid 3,4-dimethoxybenzylamide. The primary design consideration was to improve the solubility and consequently the bioavailability of the series by the addition of hydrophilic rings to the benzyl and phenyl B ring core. The synthesis of 27 cyclic, secondary amine substituted phenyl and benzyl nitrofuranyl amides is described and their activity against Mycobacterium tuberculosis reported. The series showed a strong structure-activity relationship as the benzyl nitrofuranyl amides were significantly more active than similarly substituted phenyl nitrofuranyl amides. Para-substituted benzyl piperazines showed the most antituberculosis activity. Compounds in the series were subsequently selected for bioavailability and in vivo testing. This study led to the successful discovery of novel compounds with increased antituberculosis activity in vitro and a better understanding of the requisite pharmacological properties to advance this class.

Synthesis and evaluation of nitrofuranylamides as novel antituberculosis agents.

In an effort to develop new and more potent therapies to treat tuberculosis, a library of compounds was screened for M. tuberculosis UDP-Gal mutase inhibition. Nitrofuranylamide 1 was identified as a hit in this screen, possessing good antituberculosis activity. This paper describes the synthesis and evaluation of an expanded set of nitrofuranylamides. We have discovered a number of nitrofuranylamides with submicromolar M. tuberculosis MIC values and acceptable therapeutic indexes. The MIC activity did not correlate with UDP-Gal mutase inhibition, suggesting an alternative primary cellular target was responsible for the antituberculosis activity. The compounds were only active against mycobacteria of the tuberculosis complex. On the basis of these results, four compounds were selected for in vivo testing in a mouse model of tuberculosis infection, and of these compounds one showed significant antituberculosis activity.

Nitrofurans as novel anti-tuberculosis agents: identification, development and evaluation.

During a search for new anti-tuberculosis agents, a screen of a commercially available library provided a hit nitrofuranyl amide. This hit was selected for further development due to its potential as an anti-tuberculosis agent with a novel mechanism of action, and its potential for activity against both actively growing and latent bacteria. This review covers the optimization of this lead and the strategies applied for developing this series into anti-tuberculosis agents. To optimize the hit, a series of libraries were synthesized, producing several compounds that showed increased anti-tuberculosis activity along with a strong structure activity relationship. The most active compounds from the first optimization series showed good in vitro anti-tuberculosis activity and limited in vivo efficacy, but their application was restricted due to solubility problems. Therefore, a second generation optimization library was designed and synthesized in order to increase bioavailability and solubility while maintaining good anti-tuberculosis activity. Hydrophilic cyclic secondary amines were substituted to the core scaffold and a benzyl piperazine substitution was found to be most effective in achieving improved solubility and potent anti-tuberculosis activity. However, bioactivity studies of these 2nd generation leads showed that the in vivo anti-tuberculosis activity of these compounds was limited due to rapid metabolism. Consequently, a 3rd generation of compounds was designed and synthesized in which potential sites of metabolism were blocked.