Phenytoin is associated with increased risk of osteoporosis and fragility fractures in adult epileptic patients.

INTRODUCTION: Osteoporotic fractures lead to significant decreases in the quality of life with increases in morbidity, mortality, and disability. Treatment with a variety of anti-epileptic drugs, such as phenytoin, has been understood to cause a decrease in bone mineral density. MATERIALS AND METHODS: Cohort A was identified as patients that were 18-55 years old that had epilepsy and recurrent seizures that were also prescribed phenytoin. Cohort B was identified as patients that were 18-55 years old that had epilepsy and recurrent seizures but were not prescribed phenytoin or other anti-epileptic medications. Cohorts were matched for relevant confounding pathologies and demographic factors. Outcomes were evaluated from 1 day to 5 years after the indexed event. RESULTS: A total of 35,936 patients with epilepsy that were prescribed phenytoin were matched with 109,335 patients with epilepsy that were not prescribed phenytoin. Patients on phenytoin therapy were at significantly higher risk for osteoporosis without pathological fracture, fracture of metatarsal bone, fracture of shoulder and upper arm, fracture of distal radius, fracture of thoracic vertebra, fracture of cervical vertebra, fracture of lumbar vertebra, fracture of femoral head or neck, pertrochanteric fracture, femoral shaft fracture, and distal tibia fracture (all outcomes p < 0.001). CONCLUSION: Epileptic patients on phenytoin therapy that were 18-55 years old exhibited higher associated risk of osteoporosis and osteoporotic-fragility fractures of various regions. Patients that undergo phenytoin therapy for epilepsy treatment should be educated on the increased risk of bone fractures and have appropriate lifestyle and diet modifications.

Synthesis and biological evaluation of N-alkyl sulfonamides derived from polycyclic hydrocarbon scaffolds using a nitrogen-centered radical approach.

Polycyclic hydrocarbons (PH) provide intriguing potential as lipophilic scaffolds within medicinal chemistry, but are currently limited by the availability of synthetic tools for predictable modification of the PH unit. Herein we report the development of new methods for installation of a sulfonamide unit to PH cores. In the first method, a xanthate ester serves as reagent for aminosulfonation using pre-formed imidoiodinane as N-source. An investigation of the reaction mechanism was performed to implicate a process involving a N-centered radical. An additional method for sulfonamide installation is described that involves the use of commercially available reagents and operationally convenient conditions. Using the new synthetic methods, 22 compounds were prepared and screened for biological activity against 6 mammalian cell lines along with Gram-positive and Gram-negative bacterial strains. Results of the viability assays have identified compounds that exhibit higher potency than other known anticancer agents such as indisulam and ABT-751. Additionally, the physicochemical and drug-likeness properties of the synthesized compounds have been determined experimentally and using in silico predictive tools. The initial exploration into sulfonamide insertion into PH cores has resulted in a number of compounds that warrant further development to produce molecules with therapeutic value.

PhI(OAc)2 and iodine-mediated synthesis of N-alkyl sulfonamides derived from polycyclic aromatic hydrocarbon scaffolds and determination of their antibacterial and cytotoxic activities.

The development of new approaches toward chemo- and regioselective functionalization of polycyclic aromatic hydrocarbon (PAH) scaffolds will provide opportunities for the synthesis of novel biologically active small molecules that exploit the high degree of lipophilicity imparted by the PAH unit. Herein, we report a new synthetic method for C-X bond substitution that is speculated to operate via a N-centered radical (NCR) mechanism according to experimental observations. A series of PAH sulfonamides have been synthesized and their biological activity has been evaluated against Gram-negative and Gram-positive bacterial strains (using a BacTiter-Glo assay) along with a series of mammalian cell lines (using CellTiter-Blue and CellTiter-Glo assays). The viability assays have resulted in the discovery of a number of bactericidal compounds that exhibit potency similar to other well-known antibacterials such as kanamycin and tetracycline, along with the discovery of a luciferase inhibitor. Additionally, the physicochemical and drug-likeness properties of the compounds were determined experimentally and using in silico approaches and the results are presented and discussed within.

Synthesis and identification of heteroaromatic N-benzyl sulfonamides as potential anticancer agents.

Sulfonamides are a crucial class of bioisosteres that are prevalent in a wide range of pharmaceuticals, however, the available methods for their production directly from heteroaryl aldehyde reagents remains surprisingly limited. A new approach for regioselective incorporation of a sulfonamide unit to heteroarene scaffolds has been developed and is reported within. As a result, a variety of primary benzylic N-alkylsulfonamides have been prepared via a two-step (one pot) formation from the in situ reduction of an intermediate N-sulfonyl imine under mild, practical conditions. The compounds have been screened against a variety of cell lines for cytotoxicity effects using a Cell Titer Blue assay. The cell viability investigation identifies a subset of N-benzylic sulfonamides derived from the indole scaffold to be targeted for further development into novel molecules with potential therapeutic value. The most cytotoxic of the compounds prepared, AAL-030, exhibited higher potency than other well-known anticancer agents Indisulam and ABT-751.