Suprofen

The leishmaniasis is a neglected disease caused by a group of protozoan parasites from the genus Leishmania whose treatment is limited, obsolete, toxic, and ineffective in certain cases. These characteristics motivate researchers worldwide to plan new therapeutic alternatives for the treatment of leishmaniasis, where the use of cheminformatics tools applied to computer-assisted drug design has allowed research to make great advances in the search for new drugs candidates. In this study, a series of 2-amino-thiophene (2-AT) derivatives was screened virtually using QSAR tools, ADMET filters and prediction models, allowing direct the synthesis of compounds, which were evaluated in vitro against promastigotes and axenic amastigotes of Leishmania amazonensis. The combination of different descriptors and machine learning methods led to obtaining robust and predictive QSAR models, which was obtained from a dataset composed of 1862 compounds extracted from the ChEMBL database, with correct classification rates ranging from 0.53 (for amastigotes) to 0.91 (for promastigotes), allowing to select eleven 2-AT derivatives, which do not violate Lipinski's rules, exhibit good druglikeness, and with probability ≤70% of potential activity against the two evolutionary forms of the parasite. All compounds were properly synthesized and 8 of them were shown to be active at least against one of the evolutionary forms of the parasite with IC₅₀ values lower than 10 μM, being more active than the reference drug meglumine antimoniate, and showing low or no citotoxicity against macrophage J774.A1 for the most part. Compounds 8CN and DCN-83, respectively, are the most active against promastigote and amastigote forms, with IC₅₀ values of 1.20 and 0.71 μM, and selectivity indexes (SI) of 36.58 and 119.33. Structure Activity Relationship (SAR) study was carried out and allowed to identify some favorable and/or essential substitution patterns for the leishmanial activity of 2-AT derivatives. Taken together, these findings demonstrate that the use of ligand-based virtual screening proved to be quite effective and saved time, effort, and money in the selection of potential anti-leishmanial agents, and confirm, once again that 2-AT derivatives are promising hit compounds for the development of new anti-leishmanial agents.

Dear Editor, Photoallergic reactions are classic T-cell-mediated or delayed-type hypersensitivity reactions of the skin in response to a photoallergen (or a cross-reacting chemical) to which a subject was sensitized in the past (1). The immune system recognizes the changes caused by ultraviolet (UV) radiation; it produces antibodies and causes inflammation of the skin in the exposed areas (2). Common photoallergic drugs and ingredients are included in some sunscreens, aftershave lotions, antimicrobials (especially sulfonamides), non-steroidal anti-inflammatory drugs (NSAIDs), diuretics, anticonvulsants, chemotherapy drugs, fragrances, and other hygiene products (1,3,4). A 64-year-old female patient was admitted to the Department of Dermatology and Venereology with erythema and underlining edema on her left foot (Figure 1). A few weeks earlier, the patient had had a fracture of the metatarsal bones and since then she had been taking NSAIDs systemically every day to suppress pain. Five days before being admitted to our Department, the patient started applying 2.5% ketoprofen gel to her left foot twice daily and was frequently exposed to the sun. For the last twenty years, the patient had been struggling with chronic back pain and was frequently taking different NSAIDs (ibuprofen, diclofenac, etc.). The patient also suffered from essential hypertension and was regularly taking ramipril. She was advised to discontinue ketoprofen application, avoid sunlight, and apply betamethasone cream twice daily for 7 days, which lead to complete resolution of the skin lesions in a few weeks. Two months later, we performed patch and photopatch tests to baseline series and topical ketoprofen. Only the irradiated side of the body where ketoprofen-containing gel was applied showed positive reaction to ketoprofen. Photoallergic reactions manifest as eczematous, pruritic lesions, which may spread to involve other areas of the skin that were not previously exposed to the sun (4). Ketoprofen is a nonsteroidal anti-inflammatory drug composed of a benzoylphenyl propionic acid that is commonly used both topically and systemically for the treatment of musculoskeletal diseases because of its analgesic and anti-inflammatory effects and low toxicity, but it is one of the most frequent photoallergens (1,5,6). Ketoprofen-induced photosensitivity reactions usually present as photoallergic dermatitis characterized as acute dermatitis with edema, erythema, papulovesicles, blisters, or erythema exsudativum multiforme-like lesions at the application site 1 week to 1 month after the initiation of use (7). Depending on the frequency and intensity of sun exposure, ketoprofen photodermatitis may continue or reoccur up to 1 to 14 years after discontinuing the medication (6,8). Moreover, ketoprofen contaminates clothing, shoes, and bandages, and some cases of photoallergy relapses have been reported that were induced by ketoprofen-contaminated objects after they were used again in the presence of UV radiation (5,6). Due to their similar biochemical structure, patients with ketoprofen photoallergy should avoid using some drugs such as some NSAIDs (suprofen, tiaprofenic acid), antilipidemic agent (fenofibrate) and sunscreens based on benzophenones (6,9). Physicians and pharmacists should advise patients of the potential risks when topical NSAIDs are applied on the photoexposed skin.