Coupling-Condensation Strategy for the Convergent Synthesis of an Imidazole-Fused 2-Aminoquinoline NLRP3 Agonist.

The development of a convergent route to the NLRP3 (nucleotide-binding domain and leucine-rich repeat-containing protein 3) agonist BMS-986299 is reported. The synthesis relies on a key Miyaura borylation and a tandem Suzuki-Miyaura coupling between an iodoimidazole and an o-aminochloroarene, followed by acid-mediated cyclization to afford the aminoquinoline core. The subsequent Boc cleavage and regioselective acylation afford the target compound. Two routes to the iodoimidazole intermediate are presented, along with the synthesis of the o-aminochloroarene via Negishi coupling. The convergent six-step route leads to an 80% reduction in process mass intensity compared to the linear enabling synthesis.

Amination of Nitro-Substituted Heteroarenes by Nucleophilic Substitution of Hydrogen.

An open-air method for the transition metal-free direct amination of nitro(hetero)arenes by anilines is disclosed. In this methodology, an aromatic C-H bond is substituted via oxidative nucleophilic aromatic substitution of hydrogen (ONSH). Density functional theory calculations and mechanistic studies support a dianion pathway with oxidation by molecular oxygen as the rate-limiting step.

Targeting adaptability to improve Medication Therapy Management (MTM) implementation in community pharmacy.

OBJECTIVES: (1) To develop an adaptation framework for MTM delivery for pharmacists (the MTM Adaptability Framework), (2) to examine the impact of an educational intervention informed by the MTM Adaptability Framework on MTM completion rates over a 2-year period, and (3) to explore pharmacists' perceptions regarding knowledge and beliefs about MTM and MTM implementation self-efficacy pre- and post-intervention. METHODS: This study is a prospective, mixed-methods research study including a quasi-experimental, one-group pretest-posttest quantitative study with a sequential explanatory qualitative study arm featuring semi-structured key informant interviews. US supermarket pharmacy chain setting included 93 community pharmacy sites located in Tennessee, Kentucky, and Alabama. MTM completion rates are reported as percentage of completed comprehensive medication reviews (CMRs) and targeted medication reviews (TMRs) and pharmacist perceptions. RESULTS: An 11.4% absolute increase in MTM completion rates was seen after the educational intervention targeting adaptation of MTM in the community pharmacy setting. This was found to be significant (46.92% vs. 58.3%; p < 0.001). Responses to the semi-structured interviews were mapped against CFIR and included themes: "knowledge and beliefs about MTM (pre-intervention)," "self-efficacy for MTM implementation (pre-intervention)," "knowledge and beliefs about MTM (post-intervention)," and "self-efficacy for MTM implementation (post-intervention)." Data convergence was found across these methodologies and suggested that targeting adaptability of MTM delivery increases MTM completion rates (quantitative data) and positively changes perceptions of MTM feasibility and self-efficacy (interviews). CONCLUSION: The use of an educational intervention about adaptation of MTM to influence adaptation of MTM to a chain community pharmacy setting part of an implementation strategy improved MTM completion rates significantly. Future research should investigate combined implementation strategies and their impact on MTM implementation success.

Avian Health across the Landscape: Nestling Immunity Covaries with Changing Landcover.

The landscape composition of an organism's home range or territory should influence aspects of its condition, including measures of immune function. Changes in immunocompetence arising from variation in landcover may provide important links between habitat changes and patterns of disease spread. To establish a baseline understanding for whether immune measures covary with changes in landcover, we examined associations between immunological parameters and landcover composition for adults and nestlings of five shrubland bird species. Specifically, we examined the bacteria-killing ability (BKA) of the blood plasma and profiles of the five avian leukocytes as our measures of immune function, and assessed the proportion of area around each bird's nest that was composed of the four major landcover types in the Midwestern USA: row crop agriculture, developed, forest, and grass/shrub. We performed landcover assessments at 100 and 1000 m radius buffers to identify whether associations between habitat and immune function differed at the two spatial scales. As part of this work, we examined age and species-related immunological variation, as well as associations among the immune parameters. There was little evidence linking variation in immune function to landcover composition for the adults at either spatial scale, but there were numerous associations for nestlings, and these were stronger at the 1000 than 100 m spatial scale. The proportion of grass/shrub around the nest had the largest impact on immune function, although the effect varied by immune parameter and species. BKA and basophils were inversely associated with grass/shrub for all species, whereas lymphocytes were positively associated with grass/shrub for all species. We also documented species-level differences among adults and nestlings for BKA and all leukocytes except monocytes. As expected, we found that nestlings had reduced levels of BKA, lymphocytes, monocytes, and elevated heterophils compared with adults (except for field sparrow-Spizella pusilla-nestlings, which had higher lymphocytes). Basophils generally did not differ by age class, and eosinophils exhibited species-specific patterns, in which they were higher for nestling American robins (Turdus migratorius) and gray catbirds (Dumetella carolinensis) compared with adults, but lower in the other nestlings. Heterophils and lymphocytes were inversely associated for all species and age classes, and basophil levels were positively associated with BKA across species and age classes. Together, these findings bolster our understanding of age and species-specific variation in immune function, and provide evidence that immune measures can covary with changes in landcover.

TCFH-NMI: Direct Access to N-Acyl Imidazoliums for Challenging Amide Bond Formations.

Challenging couplings of hindered carboxylic acids with non-nucleophilic amines to form amide bonds can be accomplished in high yields, and in many cases, with complete retention of the adjacent stereogenic centers using the combination of N, N, N', N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and N-methylimidazole (NMI). This method allows for in situ generation of highly reactive acyl imidazolium ions, which have been demonstrated to be intermediates in the reaction. The reagent delivers high reactivity similar to acid chlorides with the ease of use of modern uronium reagents.

Trajectories of Health-Related Quality of Life in Coronary Artery Disease.

BACKGROUND: Health-related quality of life (HRQOL) assessment is an important health outcome for measuring the efficacy of treatments and interventions for coronary artery disease (CAD). HRQOL is known to improve over the first year after interventions for CAD, but there is limited knowledge of the changes in HRQOL beyond 1 year. We investigated heterogeneity in long-term trajectories of HRQOL in patients with CAD. METHODS AND RESULTS: Data were obtained from 6226 patients identified from the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease with at least 1-vessel CAD who underwent their first catheterization between 2006 and 2009. HRQOL was assessed using the Seattle Angina Questionnaire, a 19-item disease-specific measure of HRQOL for patients with CAD. Group-based trajectory analysis was used to identify various subgroups of Seattle Angina Questionnaire trajectories over time while adjusting for missing data through a longitudinal multiple imputation model. Multinomial logistic regression was used to identify the predictors of differences among the identified subgroups. Our analysis revealed significant improvements in HRQOL across all the 5 domains of Seattle Angina Questionnaire overtime for the whole data. Multitrajectory analyses revealed 4 HRQOL trajectory subgroups including high (25.1%), largely increased (32.3%), largely decreased (25.0%), and low (17.6%) trajectories. Age, sex, body mass index, diabetes mellitus, previous history of myocardial infarction, smoking, depression, anxiety, type of treatment received, and perceived social support were significant predictors of differences among these trajectory subgroups. CONCLUSIONS: This study highlights variations in longitudinal trajectories of HRQOL in patients with CAD. Despite overall improvements in HRQOL, about a quarter of our cohort experienced a significant decline in their HRQOL over the 5-year period. Understanding these HRQOL trajectories may help personalize prognostic information, identify patients and HRQOL domains on which clinical interventions are most beneficial, and support treatment decisions for patients with CAD.

Residents Teaching Residents: Results of an Interdisciplinary Educational Endeavor.

OBJECTIVES: Resident physicians across disciplines are engaged in teaching at multiple levels. Available literature focuses on medical student education and intra-disciplinary teaching. The national shortage of psychiatrists coupled with an increasing mental illness burden necessitates development of creative interdisciplinary collaboration. The authors report on an interdisciplinary, resident-to-resident didactic series assessing whether such a model could improve internal medicine resident comfort with managing psychiatric illness on inpatient medical wards. METHODS: Internal medicine residents were assessed regarding their comfort level with managing certain common inpatient psychiatric presentations before and after the delivery of a teaching curriculum designed and delivered by psychiatry residents. RESULTS: Internal medicine residents' overall confidence with identifying and managing common psychiatric problems on inpatient medical wards improved. Comfort level with managing depression and demoralization and determining decisional capacity both improved to a statistically significant degree. CONCLUSIONS: Collaborative, interdisciplinary care is complex and its benefits can be difficult to assess. Data from this study showed that interdisciplinary teaching at the resident level has the potential to be an effective means for building collaboration and can lead to a subjective improvement in comfort managing common inpatient psychiatric presentations on medical wards. Additionally, qualitative observations suggest that such an intervention can improve interdisciplinary collaboration.

Incidence and Prognostic Implications of Late Bleeding After Myocardial Infarction or Unstable Angina According to Treatment Strategy.

BACKGROUND: Bleeding complications accompanying coronary revascularization are associated with increased mortality; however, few data are available on subsequent bleeding risk. We used administrative data to assess the incidence of late bleeding events in patients with acute coronary syndrome (ACS) according to treatment allocation. METHODS: The cohort and bleeding events were identified through the Canadian Institute for Health Information discharge abstract database. Crude and adjusted odds ratios (ORs) were calculated for index and postindex admission bleeding up to 1 year after discharge. RESULTS: Of 31,941 patients hospitalized with ACS, 7681 (32.4%) patients were treated with medication alone, 3728 (15.2%) underwent angiography without intervention, and 13,075 (53.4%) underwent percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). The overall incidence of readmission with bleeding based on administrative codes was low (3.8% for medically treated patients, 2.8% for patients who underwent angiography alone, 2.6% for patients who underwent CABG, and 1.8% for patients who underwent PCI; P < 0.0001). Bleeding codes were mainly gastrointestinal bleeding (52%), but 7.8% were intracranial episodes of bleeding. Patients who received PCI had significantly lower odds of late bleeding compared with medically treated patients (OR, 0.76; 95% CI, 0.62-0.94). Late bleeding during the first year after ACS was associated with mortality (OR, 4.96; 95% CI, 2.47-9.93). CONCLUSIONS: Patients who underwent revascularization procedures had a relatively low risk for late bleeding events after a hospitalization for ACS. Late bleeding events were associated with an increased risk of death.

4-Cyanobenzenesulfonamides: Amine Synthesis and Protecting Strategy To Compliment the Nosyl Group.

4-Cyanobenzenesulfonamides of secondary amines were found to cleave to the parent amine cleanly under the action of thiol and base. This feature readily lends itself to the use of this motif as an amine protecting/activating group within a broader context of amine synthesis. The crystalline sulfonamides could be further elaborated by alkylation and arylation similarly to nitrobenzenesulfonamides. The sulfonamides could withstand conditions that functionalize nitroarenes, such as reductions and vicarious nucleophilic substitution reactions.

Area Median Income and Metropolitan Versus Nonmetropolitan Location of Care for Acute Coronary Syndromes: A Complex Interaction of Social Determinants.

BACKGROUND: Metropolitan versus nonmetropolitan status and area median income may independently affect care for and outcomes of acute coronary syndromes. We sought to determine whether location of care modifies the association among area income, receipt of cardiac catheterization, and mortality following an acute coronary syndrome in a universal health care system. METHODS AND RESULTS: We studied a cohort of 14 012 acute coronary syndrome patients admitted to cardiology services between April 18, 2004, and December 31, 2011, in southern Alberta, Canada. We used multivariable logistic regression to determine the odds of cardiac catheterization within 1 day and 7 days of admission and the odds of 30-day and 1-year mortality according to area median household income quintile for patients presenting at metropolitan and nonmetropolitan hospitals. In models adjusting for area income, patients who presented at nonmetropolitan facilities had lower adjusted odds of receiving cardiac catheterization within 1 day of admission (odds ratio 0.22, 95% CI 0.11-0.46, P<0.001). Among nonmetropolitan patients, when examined by socioeconomic status, each incremental decrease in income quintile was associated with 10% lower adjusted odds of receiving cardiac catheterization within 7 days (P<0.001) and 24% higher adjusted odds of 30-day mortality (P=0.008) but no significant difference for 1-year mortality (P=0.12). There were no differences in adjusted mortality among metropolitan patients. CONCLUSION: Within a universal health care system, the association among area income and receipt of cardiac catheterization and 30-day mortality differed depending on the location of initial medical care for acute coronary syndromes. Care protocols are required to improve access to care and outcomes in patients from low-income nonmetropolitan communities.

Daily racial microaggressions and ethnic identification among Native American young adults.

The current study investigated 114 Native American young adults' experiences of racial microaggressions, and links between microaggression experiences and self-reported ethnic and cultural identification. Microaggressions were assessed using the Daily Racial Microaggressions Scale, Short Form (DRM). Ethnic identity and cultural participation were assessed using the Multigroup Ethnic Identity Measure (MEIM) and the Orthogonal Cultural Identification Scale (OCIS). Participants reported strong identification with their Native/indigenous ethnicity, along with stronger commitment than exploration on the 2 MEIM subscales. On the OCIS, participants reported moderately strong identification with Native culture and practices, with strong identification with White American culture. Females reported higher White identification than males, and females also reported significantly stronger identification with White culture than Native. On the DRM, 98% of participants reported experiencing at least 1 type of racial microaggression. Generally, the extent to which participants were upset by the microaggressions was mild, but all types of microaggressions received ratings from not upsetting at all to extremely upsetting. Microinvalidations were significantly more upsetting than microinsults for females, but there was no difference among the forms of microaggression for males. Correlational findings demonstrated that greater Native identification was strongly associated with more microaggression experiences, especially among males. Regression analyses found several identity correlates of microaggression experiences. "Assumption of criminality" and "assumed superiority of White values" were most frequently associated with identity scales. Results are discussed within the context of identity development theory.

Sex, socioeconomic status, access to cardiac catheterization, and outcomes for acute coronary syndromes in the context of universal healthcare coverage.

BACKGROUND: Sex and neighborhood socioeconomic status (nSES) may independently affect the care and outcomes of acute coronary syndrome, partly through barriers in timely access to cardiac catheterization. We sought to determine whether sex modifies the association between nSES and the receipt of cardiac catheterization and mortality after an acute coronary syndrome in a universal healthcare system. METHODS AND RESULTS: We studied 14 012 patients with acute coronary syndrome admitted to cardiology services between April 18, 2004, and December 31, 2011, in Southern Alberta, Canada. We used multivariable logistic regression to compare the odds of cardiac catheterization within 2 and 30 days of admission and the odds of 30-day and 1-year mortality for men and women by quintile of neighborhood median household income. Significant relationships between nSES and the receipt of cardiac catheterization and mortality after acute coronary syndrome were detected for women but not men. When examined by nSES, each incremental decrease in neighborhood income quintile for women was associated with a 6% lower odds of receiving cardiac catheterization within 30 days (P=0.01) and a 14% higher odds of 30-day mortality (P=0.03). For men, each decrease in neighborhood income quintile was associated with a 2% lower odds of receiving catheterization within 30 days (P=0.10) and a 5% higher odds of 30-day mortality (P=0.36). CONCLUSIONS: Associations between nSES and receipt of cardiac catheterization and 30-day mortality were noted for women but not men in a universal healthcare system. Care protocols designed to improve equity of access to care and outcomes are required, especially for low-income women.

Effect of systemic blockade of α(1)-noradrenergic receptors on sex behavior and vaginal-cervical stimulation-induced Fos in female rats.

It is hypothesized that systemic α1-noradrenergic antagonists may interfere with the transmission of sensory stimulation, particularly vaginal--cervical stimulation (VCS), which is crucial for reproductive functioning. To determine if α1-noradrenergic transmission receptor activity is necessary for transmission of sensory information important for VCS-dependent events, we conducted an experiment using prazosin, a α1-noradrenergic receptor antagonist. First, three doses of prazosin (1.0, 0.5 or 0.1 mg/kg) or the 10% ETOH in sesame oil vehicle were administered i.p. and sexual receptivity was assessed 30 min later in ovariectomized, hormone-treated female rats. The 1 mg/kg dose of prazosin significantly inhibited lordosis quotients and lordosis ratings. This dose of prazosin (1.0 mg/kg) was then administered 30 min prior to VCS or control scapular stimulation (CSS) and Fos-IR was examined in the posterodorsal medial amygdala (MeaPD), the medial preoptic area (mPOA), and the rostral ventromedial hypothalamus (rVMH). VCS significantly increased Fos-IR in all of the brain areas examined. Prazosin treatment inhibited the increase in Fos-IR in the mPOA and MeaPD but not in the rVMH. These results suggest that administration of systemic prazosin may selectively affect sensory inputs to the mPOA and MeaPD and these inputs are relevant for the control of female sexual behaviors by peripheral α1-noradrenergic activity.

A 21st century HPLC workflow for process R&D.

A unique high-performance liquid chromatographic (HPLC) workflow specifically designed for the rigors of process development has been developed. A key feature of the workflow is the creation of an HPLC software-hardware platform designed to automatically and systematically screen samples using a matrix of columns and eluents to aggressively search for impurities. The workflow platform was assembled from commercial hardware components and both custom and commercial HPLC software. The platform can be used to challenge existing HPLC methods or to develop new methods. Three real world examples are provided to illustrate the utility of the platform to rigorously assess the complexity of samples and to develop new and improved HPLC methods.

Response to host volatiles by native and introduced populations of Dendroctonus valens (Coleoptera: Curculionidae, Scolytinae) in North America and China.

Bark beetles (Coleoptera: Curculionidae, Scolytinae) have specialized feeding habits, and commonly colonize only one or a few closely related host genera in their geographical ranges. The red turpentine beetle, Dendroctonus valens LeConte, has a broad geographic distribution in North America and exploits volatile cues from a wide variety of pines in selecting hosts. Semiochemicals have been investigated for D. valens in North America and in its introduced range in China, yielding apparent regional differences in response to various host volatiles. Testing volatiles as attractants for D. valens in its native and introduced ranges provides an opportunity to determine whether geographic separation promotes local adaptation to host compounds and to explore potential behavioral divergence in native and introduced regions. Furthermore, understanding the chemical ecology of host selection facilitates development of semiochemicals for monitoring and controlling bark beetles, especially during the process of expansion into new geographic ranges. We investigated the responses of D. valens to various monoterpenes across a wide range of sites across North America and one site in China, and used the resulting information to develop an optimal lure for monitoring populations of D. valens throughout its Holarctic range. Semiochemicals were selected based on previous work with D. valens: (R)-(+)-alpha-pinene, (S)-(-)-alpha-pinene, (S)-(-)-beta-pinene, (S)-(+)-3-carene, a commercially available lure [1:1:1 ratio of (R)-(+)-alpha-pinene:(S)-(-)-beta-pinene:(S)-(+)-3-carene], and a blank control. At the release rates used, (+)-3-carene was the most attractive monoterpene tested throughout the native range in North America and introduced range in China, confirming results from Chinese studies. In addition to reporting a more effective lure for D. valens, we present a straightforward statistical procedure for analysis of insect trap count data yielding cells with zero counts, an outcome that is common but makes the estimation of the variance with a Generalized Linear Model unreliable because of the variability/mean count dependency.

The prognostic importance of nonsignificant left main coronary artery disease in patients undergoing percutaneous coronary intervention.

OBJECTIVES: The purpose of this research was to study the association between nonsignificant (<50%) left main coronary artery disease (LMCAD) and short- and long-term survival in patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: The prognostic importance of nonsignificant LMCAD is unknown; however, the co-existence of nonsignificant LMCAD may influence revascularization decisions. METHODS: We analyzed mortality and repeat catheterization rates of 11,855 patients in a prospective cardiac registry database who underwent single-vessel or multivessel PCI from January 1996 through December 2001. Of this cohort, 11.7% (n = 1,385) had nonsignificant (<50%) LMCAD. Outcomes were compared with those without LMCAD. A secondary analysis was performed on a larger cohort of 34,586 patients undergoing cardiac catheterization, irrespective of mode of revascularization therapy. RESULTS: Patients with nonsignificant LMCAD had more co-morbidities, and a significantly higher crude mortality rate at 1 year compared with those without LMCAD (4.4% vs. 3.4%; p = 0.05). The 7-year crude mortality hazard ratio (HR) of PCI patients with <50% LMCAD versus those with no LMCAD was 1.18 (95% confidence interval [CI] 0.94 to 1.46). After risk adjustment for differences in baseline clinical profile, however, the HR decreased to 0.98 (95% CI 0.79 to 1.23). Repeat catheterization rates at 1 year did not differ between groups. The secondary analysis in all patients with nonsignificant LMCAD showed an adjusted HR of 1.03 (95% CI 0.94 to 1.14). CONCLUSIONS: Patients undergoing single-vessel or multivessel PCI who have <50% LMCAD have a nonsignificantly increased 18% relative risk for mortality compared with those without detectable LMCAD that appears to be related to these patients' higher incidence of co-morbidities rather than the left main stenosis itself.

1-Deoxy-D-xylulose 5-phosphate reductoisomerase (IspC) from Mycobacterium tuberculosis: towards understanding mycobacterial resistance to fosmidomycin.

1-Deoxy-d-xylulose 5-phosphate reductoisomerase (IspC) catalyzes the first committed step in the mevalonate-independent isopentenyl diphosphate biosynthetic pathway and is a potential drug target in some pathogenic bacteria. The antibiotic fosmidomycin has been shown to inhibit IspC in a number of organisms and is active against most gram-negative bacteria but not gram positives, including Mycobacterium tuberculosis, even though the mevalonate-independent pathway is the sole isopentenyl diphosphate biosynthetic pathway in this organism. Therefore, the enzymatic properties of recombinant IspC from M. tuberculosis were characterized. Rv2870c from M. tuberculosis converts 1-deoxy-d-xylulose 5-phosphate to 2-C-methyl-d-erythritol 4-phosphate in the presence of NADPH. The enzymatic activity is dependent on the presence of Mg(2+) ions and exhibits optimal activity between pH 7.5 and 7.9; the K(m) for 1-deoxyxylulose 5-phosphate was calculated to be 47.1 microM, and the K(m) for NADPH was 29.7 microM. The specificity constant of Rv2780c in the forward direction is 1.5 x 10(6) M(-1) min(-1), and the reaction is inhibited by fosmidomycin, with a 50% inhibitory concentration of 310 nM. In addition, Rv2870c complements an inactivated chromosomal copy of IspC in Salmonella enterica, and the complemented strain is sensitive to fosmidomycin. Thus, M. tuberculosis resistance to fosmidomycin is not due to intrinsic properties of Rv2870c, and the enzyme appears to be a valid drug target in this pathogen.

Development of a scintillation proximity assay for the Mycobacterium tuberculosis KasA and KasB enzymes involved in mycolic acid biosynthesis.

Tuberculosis remains a global health problem, and programs dedicated to discovery of novel compounds against Mycobacterium tuberculosis require robust assays for high-throughput screening of chemical and natural product libraries. Enzymes involved in the biosynthesis of mycolic acids, vital components of the mycobacterial cell wall, have received much attention as potential drug targets. KasA and KasB, examples of the beta-ketoacyl-acyl carrier protein synthase I/II (KASI/II) class of condensing enzymes of the M. tuberculosis fatty acid synthase II system have been the focus of several studies designed to biochemically characterize these enzymes. Whilst robust methods have been developed for FabH-like proteins, fast and sensitive assays for high-throughput screening of KASI/II enzymes have not been available. Here we report the development of a direct scintillation proximity assay (SPA) for the KASI/II enzymes, KasA and KasB. The SPA was more sensitive than existing assays, as shown by its ability to measure activity using less enzyme than other assay formats, and the SPA was validated using the known KAS inhibitor thiolactomycin. In addition, the KasA and KasB SPA was adapted for use with Staphylococcus aureus FabF to show the versatility of this assay format to KAS enzymes from other pathogenic organisms.

Acetylene-based analogues of thiolactomycin, active against Mycobacterium tuberculosis mtFabH fatty acid condensing enzyme.

Analogues of the natural antibiotic thiolactomycin, with acetylene-based side chains, have the highest recorded in vitro inhibitory activity against the recombinant Mycobacterium tuberculosis beta-ketoacyl-ACP synthase mtFabH condensing enzyme. In particular, 5-[3-(4-acetyl-phenyl)-prop-2-ynyl]-4-hydroxy-3,5-dimethyl-5H-thiophen-2-one exhibited more than an 18-fold increased potency, compared to thiolactomycin, against this key condensing enzyme, involved in M. tuberculosis mycolic acid biosynthesis. Analogues of the antibiotic thiolactomycin, with acetylene-based side chains, have the highest recorded activity against cloned mtFabH condensing enzyme.

Biphenyl-based analogues of thiolactomycin, active against Mycobacterium tuberculosis mtFabH fatty acid condensing enzyme.

Analogues of the antibiotic thiolactomycin, with biphenyl-based 5-substituents, were found to have excellent in vitro inhibitory activity against the recombinant Mycobacterium tuberculosis beta-ketoacyl-ACP synthase mtFabH condensing enzyme. In particular, 5-(4'-benzyloxy-biphen-4-ylmethyl)-4-hydroxy-3,5-dimethyl-5H-thiophen-2-one exhibited approximately a 4-fold increased potency against this key condensing enzyme involved in M. tuberculosis mycolic acid biosynthesis, compared to thiolactomycin.