CT imaging of complications of aortic intramural hematoma: a pictorial essay.

Aortic intramural hematoma (IMH) is a pathologic process with a clinical presentation identical to aortic dissection and associated with significant morbidity and mortality. Radiologists must be familiar with the imaging appearances of IMH as computed tomography (CT) plays a critical role in both diagnosis and patient management. The course of IMH is variable and the process may regress, remain stable, or progress in extent and therefore imaging findings associated with a negative prognosis must be recognized and included in the formal radiology report. Potentially life-threatening complications and findings associated with IMH include hemopericardium and cardiac tamponade, coexisting aortic dissection, ulcer-like projection, intramural blood pool, and extension of hematoma along the pulmonary or coronary arteries, which are identifiable with aortic protocol CT. The purpose of this pictorial review is to provide the reader with an image-based review of the diagnostic criteria, related complications, and associated critical prognostic features in patients presenting with aortic IMH.

Hamartomas from head to toe: an imaging overview.

Hamartomas are tumours composed of mesenchymal tissues such as cartilage, fat, connective tissue and smooth muscle and can be found in virtually any organ system. These masses commonly develop sporadically, but are also seen in certain syndromes such as tuberous sclerosis or Carney triad. While their imaging appearance varies depending on the organ they arise from, findings are usually unique and a diagnosis can be confidently made. Radiologists must be aware of the clinical and imaging presentations of these lesions with the particular goal of avoiding unnecessary studies or invasive procedures. Furthermore, knowledge of common syndromic entities is crucial, as the radiologist may be the first to suggest the diagnosis.

Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor.

Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb), but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR) and extensively (XDR) drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment.

New direct inhibitors of InhA with antimycobacterial activity based on a tetrahydropyran scaffold.

Tetrahydropyran derivative 1 was discovered in a high-throughput screening campaign to find new inhibitors of mycobacterial InhA. Following initial in-vitro profiling, a structure-activity relationship study was initiated and a focused library of analogs was synthesized and evaluated. This yielded compound 42 with improved antimycobacterial activity and low cytotoxicity. Additionally, the crystal structure of InhA in complex with inhibitor 1 was resolved, to reveal the binding mode and provide hints for further optimization.

Release of 50 new, drug-like compounds and their computational target predictions for open source anti-tubercular drug discovery.

As a follow up to the antimycobacterial screening exercise and the release of GSK´s first Tres Cantos Antimycobacterial Set (TCAMS-TB), this paper presents the results of a second antitubercular screening effort of two hundred and fifty thousand compounds recently added to the GSK collection. The compounds were further prioritized based on not only antitubercular potency but also on physicochemical characteristics. The 50 most attractive compounds were then progressed for evaluation in three different predictive computational biology algorithms based on structural similarity or GSK historical biological assay data in order to determine their possible mechanisms of action. This effort has resulted in the identification of novel compounds and their hypothesized targets that will hopefully fuel future TB drug discovery and target validation programs alike.

Design, synthesis, and evaluation of new thiadiazole-based direct inhibitors of enoyl acyl carrier protein reductase (InhA) for the treatment of tuberculosis.

Mycobacterial enoyl acyl carrier protein reductase (InhA) is a clinically validated target for the treatment of tuberculosis infections, a disease that still causes the death of at least a million people annually. A known class of potent, direct, and competitive InhA inhibitors based on a tetracyclic thiadiazole structure has been shown to have in vivo activity in murine models of tuberculosis infection. On the basis of this template, we have here explored the medicinal chemistry of truncated analogues that have only three aromatic rings. In particular, compounds 8b, 8d, 8f, 8l, and 8n show interesting features, including low nanomolar InhA IC50, submicromolar antimycobacterial potency, and improved physicochemical profiles in comparison with the tetracyclic analogues. From this series, 8d is identified as having the best balance of potency and properties, whereby the resolved 8d S-enatiomer shows encouraging in vivo efficacy.

Encoded library technology as a source of hits for the discovery and lead optimization of a potent and selective class of bactericidal direct inhibitors of Mycobacterium tuberculosis InhA.

Tuberculosis (TB) is one of the world's oldest and deadliest diseases, killing a person every 20 s. InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis, is the target of the frontline antitubercular drug isoniazid (INH). Compounds that directly target InhA and do not require activation by mycobacterial catalase peroxidase KatG are promising candidates for treating infections caused by INH resistant strains. The application of the encoded library technology (ELT) to the discovery of direct InhA inhibitors yielded compound 7 endowed with good enzymatic potency but with low antitubercular potency. This work reports the hit identification, the selected strategy for potency optimization, the structure-activity relationships of a hundred analogues synthesized, and the results of the in vivo efficacy studies performed with the lead compound 65.

Discovery of novel InhA reductase inhibitors: application of pharmacophore- and shape-based screening approach.

BACKGROUND: InhA is a promising and attractive target in antimycobacterial drug development. InhA is involved in the reduction of long-chain trans-2-enoyl-ACP in the type II fatty acid biosynthesis pathway of Mycobacterium tuberculosis. Recent studies have demonstrated that InhA is one of the targets for the second line antitubercular drug ethionamide. RESULTS: In the current study, we have generated quantitative pharmacophore models using known InhA inhibitors and validated using a large test set. The validated pharmacophore model was used as a query to screen an in-house database of 400,000 compounds and retrieved 25,000 hits. These hits were further ranked based on its shape and feature similarity with potent InhA inhibitor using rapid overlay of chemical structures (OpenEye™) and subsequent hits were subjected for docking. Based on the pharmacophore, rapid overlay of chemical structures model and docking interactions, 32 compounds with more than eight chemotypes were selected, purchased and assayed for InhA inhibitory activity. Out of the 32 compounds, 28 demonstrated 10-38% inhibition against InhA at 10 µM. CONCLUSION: Further optimization of these analogues is in progress and will update in due course.

Fueling open-source drug discovery: 177 small-molecule leads against tuberculosis.

With the aim of fuelling open-source, translational, early-stage drug discovery activities, the results of the recently completed antimycobacterial phenotypic screening campaign against Mycobacterium bovis BCG with hit confirmation in M. tuberculosis H37Rv were made publicly accessible. A set of 177 potent non-cytotoxic H37Rv hits was identified and will be made available to maximize the potential impact of the compounds toward a chemical genetics/proteomics exercise, while at the same time providing a plethora of potential starting points for new synthetic lead-generation activities. Two additional drug-discovery-relevant datasets are included: a) a drug-like property analysis reflecting the latest lead-like guidelines and b) an early lead-generation package of the most promising hits within the clusters identified.