thiosildenafil and Erectile-Dysfunction

In this study, four unapproved analogues of Sildenafil (SDF) were photodegraded under synthetic sunlight in artificial freshwater. Homosildenafil (H-SDF), hydroxyhomo-sildenafil (HH-SDF), norneosildenafil (NR-SDF) and thiosildenafil (T-SDF) were selected because they are frequently detected as adulterants in natural herbal products. Using UPLC-Orbitrap (Q Exactive)-MS, six photoproducts common to H-SDF, HH-SDF and T-SDF and nine unique transformation products of different molecular weights were identified based on their high-resolution (+)ESI product ion spectra. Mass spectral analysis of deuterated H-SDF, labeled on the N-ethyl group, allowed to gain mechanistic insight into the fragmentation pathway of the substituted piperazine ring and to support the postulated photoproduct structures. The mass spectral fragmentation confirmed the stepwise destruction of the piperazine ring eventually producing a sulfonic acid derivative (C17 H20 N4 O5 S: 392.1151 Da). In contrast, the photodegradation of NR-SDF, which lacks a piperazine ring in its structure, formed only two prominent photoproducts originating from N,N-dealkylation of the sulfonamide followed by hydrolysis. The current work constitutes the first study on the photodegradation of analogs of erectile dysfunction drugs and the first detection of two transformation products (m/z 449 and 489) in environmental samples.

Topics: Erectile Dysfunction; Fresh Water; Humans; Male; Photolysis; Piperazine; Piperazines; Purines; Pyrimidines; Sildenafil Citrate; Spectrometry, Mass, Electrospray Ionization; Sulfonamides; Sulfones; Sunlight; Tandem Mass Spectrometry; Vasodilator Agents; Wastewater; Water Pollutants, Chemical

Two analogues of sildenafil were detected in herbal dietary supplements marketed as aphrodisiacs. Both compounds were identified as thioketone analogues of sildenafil in which the carbonyl group in the pyrimidine ring of sildenafil was substituted with a thiocarbonyl group. The first compound was identified as thiosildenafil, a compound that has recently been reported as an adulterant in health supplements. The structure of the second compound was established using LC-MS, UV spectroscopy, ESI-MS(n), NMR and a hydrolytic process. A detailed study of the hydrolysis products of sildenafil, thiosildenafil, and the second unknown compound proved that the second compound, named thiomethisosildenafil, had a structure analogous to sildenafil in which the N-methylpiperazine moiety had been replaced with 2,6-dimethylpiperazine and the oxygen atom of the carbonyl group in the heterocyclic ring had been replaced with a sulfur atom. Under the hydrolytic reaction conditions employed in this study, thioketones hydrolyze to ketones (e.g., thiosildenafil-->sildenafil), making this a valuable technique for the structure elucidation of thiosildenafil analogues. Ten herbal dietary supplements, each as a capsule dosage form, were found to contain 8-151 mg of thiomethisosildenafil per capsule, and one herbal dietary supplement was found to contain 35 mg of thiosildenafil per capsule.

Topics: Aphrodisiacs; Chromatography, Liquid; Dietary Supplements; Drug Contamination; Erectile Dysfunction; Food Contamination; Humans; Hydrolysis; Ketones; Male; Mass Spectrometry; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Phosphodiesterase Inhibitors; Piperazines; Purines; Pyrimidines; Sildenafil Citrate; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Ultraviolet; Sulfones