Design and synthesis of 5-aryl-pyridone-carboxamides as inhibitors of anaplastic lymphoma kinase

Anaplastic lymphoma kinase (ALK) is a promising new target for therapy of certain cancers such as anaplastic large-cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT). We have identified a series of novel pyridones as kinase inhibitors of ALK by application of a stepwise process involving in vitro screening of a novel targeted library followed by iterative template modification based on medicinal chemistry insights and computational ranking of virtual libraries. Using this process, we discovered ALK-selective inhibitors with improved potency and selectivity. Herein the details of the design process and synthesis of these novel pyridones, along with their enzymatic and cell-based activity, are discussed.     

Synthesis, antimicrobial and anticancer activity of new thiosemicarbazone derivatives

Thiosemicarbazones of p-aminobenzoic acid (PABA) were synthesized and tested for their antimicrobial and anticancer activity. Hydroxamate derivatives 4a-4l were found to have better antimicrobial and anticancer activity than their acid counterpart. Compound 4d was found to have good antimicrobial activity against Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Vibrio cholerae, and Bacillus subtilis with IC(50) value of about 1 μM. Compound 4f showed potent antifungal activity against Candida albicans (IC(50) = 1.29 μM) and compound 4h showed potent anticancer activity (IC(50) = 0.07 μM).     

Aspirin resistance

Aspirin reduces the odds of serious atherothrombotic vascular events and death in a broad category of high risk patients by about one quarter. The term 'aspirin resistance' has been used to describe not only an absence of the expected pharmacologic effects of aspirin on platelets but also poor clinical outcomes, such as recurrent vascular events, in patients treated with aspirin. Various factors such as genetic, nonadherence, variable response to different doses, co-morbid conditions and drug interactions are responsible for aspirin resistance. Many methods, with their limitations, are available to measure the effects on platelets. Despite treatment failures, aspirin remains the single most cost-effective drug for the secondary prevention of atherothrombotic disease. To optimize its clinical effectiveness, clinicians should be aware of the potential causes of aspirin treatment failure, prescribe aspirin in appropriate doses, and encourage patients to take aspirin, stop smoking, and avoid regular use of NSAIDs.     

Aniridia-Wilms' tumour syndrome--a case report.

Wilms' tumour is rarely associated with sporadic non-familial congenital aniridia. A child with sporadic aniridia has a 25% chance of subsequently developing Wilms' tumour. Unawareness of this association can lead to a delayed diagnosis of Wilms' tumour. One such case in a 2 year old is reported. Wilms' tumour, one of the common childhood malignancies, is associated with other congenital anomalies in about 15% of cases. These include hemihypertrophy, genitourinary abnormalities, mental retardation, aniridia etc. Sporadic non-familial aniridia was noted in only 1.1% of 547 children with Wilms' tumours evaluated by the National Wilms' Tumour study group. Unawareness on the part of a clinician about these associated anomalies can lead to an avoidable delay in diagnosing Wilms' tumour. One such case in a two year old girl is being reported.