Let's imagine a future in which medications not only fight diseases but do so more effectively and with fewer doses. This is not a distant future scenario; It is a potential reality that will be brought closer by improving the way drugs interact with our bodies. A recent study investigates the subtle art of altering drug molecules, focusing on a drug component known as acedoben, used in the antiviral drug inosine pranobex. By adding fluorine atoms to the molecular structure of acedoben, researchers have revealed significant changes in its characteristics, potentially revolutionizing its effectiveness and how quickly our body can use it.
Recent research by Dr. Thomas Shell and Joshua Boldon of the Department of Chemistry and Physics at Lincoln Memorial University explores the profound effects of fluorine substitution on the characteristics of the pharmacological compound acedoben, a key ingredient of the antiviral drug inosine pranobex. Their findings, published in Results in Chemistry, highlight significant improvements in the way the body can absorb the trifluoroacetamide derivative of acedoben, offering promising implications for drug design and effectiveness.
Acedoben plays a crucial role in the formulation of inosine pranobex, used to combat various viral infections. The introduction of fluorine transforms acedoben into a new derivative, 3F-AcPABA, which shows clear advantages over the parent molecule in terms of how the body can process and use the drug.
Their research shows that 3F-AcPABA is seven times more capable of fusing with fats than AcPABA. This increased capacity suggests that 3F-AcPABA could more efficiently transit biological barriers, particularly at the typical acidic levels of the stomach, where drug absorption into the bloodstream begins. This feature is crucial as it potentially increases the availability of the drug in the body, meaning that more of the drug can circulate and have an active effect.
Additionally, the study examines how the electron withdrawal effect of fluorine atoms affects the electronic distribution within the molecule, influencing several properties, including acidity and the nature of the carbonyl bond. Interestingly, despite these chemical modifications, the acidity levels of the carboxylic acid groups in AcPABA and 3F-AcPABA remained almost unchanged, highlighting the subtlety of the structural changes involved.
Dr. Shell provided insight into the broader implications of his findings. “Our results demonstrate that even minor chemical modifications can substantially alter the physical properties of a molecule in ways that improve its therapeutic potential. This may lead to more effective drugs with a greater ability to passively cross biological barriers,” he explained.
The implications of this research extend beyond acedoben. For example, Dr. Thomas Shell and Joshua Boldon recently reported on the physicochemical properties of the trifluoroacetamide derivative of paracetamol. Dr. Shell is currently exploring the effects of fluorine substitution on the physicochemical properties of other small molecule drugs. Current research contributes to a growing body of knowledge supporting the strategic use of fluorine in drug design, helping to optimize drug properties for improved clinical outcomes. This study is a cornerstone for future research aimed at harnessing the full potential of fluorine in pharmaceutical development.
Magazine reference
Joshua A. Boldon, Thomas A. Shell, “Physicochemical properties of acedoben and its trifluoroacetamide derivative,” Results in Chemistry, 2023. DOI: https://doi.org/10.1016/j.rechem.2023.101075
Joshua A. Boldon, Thomas A. Shell, “Physicochemical properties and kinetics of cytochromes P-450 from a trifluoroacetamide derivative of acetaminophen,” Results in Chemistry, 2023. DOI: https://doi.org/10.1016/j.rechem.2023.101129
About the Author
Thomas Shell He was born and raised in central Pennsylvania. He earned a bachelor's degree in chemistry and biology from the University of Richmond, where he conducted undergraduate research on the synthesis of pyrroles using vinylogenic iminium salts with Stuart Clough and John Gupton. As a graduate student at Emory University under Debra Mohler, she synthesized and studied light-sensitive organometallic complexes that cleave DNA. He was a visiting assistant professor at Franklin and Marshall College before becoming an assistant professor at West Virginia State University, where he studied the microwave-assisted organic synthesis of succinimides and maleimides. He was a postdoctoral associate with David Lawrence at the University of North Carolina and a research assistant professor at the UNC Eshelman School of Pharmacy, where he studied cobalamins as light-sensitive compounds for manipulation of biological systems. He discovered that hydroxocobalamin catalytically generates hydroxyl radicals upon ultraviolet light illumination in the presence of oxygen. Furthermore, he discovered that alkylcobalamins respond to infrared light wavelengths by conjugating with an appropriate fluorophore. This discovery is important for the development of molecules that respond to the wavelengths of light within the tissue's optical window, wavelengths that penetrate deeper into the tissue. Molecules that respond to wavelengths of light within the optical window of tissue are critical to using photoresponsive molecules for targeted treatment of diseases. As an assistant professor at Saint Anselm College and as an assistant professor at Norwich University, he studied the ability of alkylcobalamins to cleave DNA and release anticancer drugs in response to visible light and x-ray exposure. At Lincoln Memorial University continues to synthesize alkylcobalamin anticancer drug conjugates and investigate the physicochemical properties of fluorinated drug derivatives, which generally have improved lipophilicity relative to the parent molecule. He is an associate professor of chemistry at Lincoln Memorial University.
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