Acetylsalicylic acid-sulfa drugs conjugates as potential urease inhibitors and anti-inflammatory agents: bio-oriented drug synthesis, molecular docking, and dynamics simulation studies

Article

Author: Yousaf, Numan ; Imran, Muhammad ; Muddassar, Muhammad ; Asari, Asnuzilawati ; Hameed, Abdul ; Ahmed, Mahmood ; Abdul Qadir, Muhammad ; Ahmad, Saghir

To explore the new mode of action and reduce side effects, making conjugates of existing drugs is becoming an attractive tool in the realm of medicinal chemistry. In this work, we exploited this approach and synthesized new conjugates to assess their activities against the enzymes involved in different pathological conditions. Specifically, we design and synthesized conjugates involving acetylsalicylic acid and sulfa drugs, validating the newly crafted conjugates using techniques like IR, ¹HNMR, ¹³CNMR, and elemental analysis. These conjugates underwent assessment for their ability to inhibit cyclooxygenase-2 (COX-2), urease enzymes, and their anti-inflammatory potential. A competitive mode of urease inhibition was observed for acetylsalicylic acid conjugated with sulfanilamide, sulfacetamide, and sulfadiazine with IC₅₀ of 2.49 ± 0.35 µM, 6.21 ± 0.28 µM, and 6.57 ± 0.44 µM, respectively. Remarkably, the acetylsalicylic acid-sulfamethoxazole conjugate exhibited exceptional anti-inflammatory activity, effectively curtailing induced edema by 83.7%, a result akin to the reference anti-inflammatory drug indomethacin's performance (86.8%). Additionally, it demonstrated comparable COX-2 inhibition (75.8%) to the reference selective COX-2 inhibitor celecoxib that exhibited 77.1% inhibition at 10 µM concentration. To deepen our understanding, we employed molecular docking techniques to predict the binding interactions of competitive inhibitors with COX-2 and urease receptors. Additionally, MD simulations were carried out, confirming the stability of inhibitor-target complexes throughout the simulation period, devoid of significant conformational changes. Collectively, our research underscores the potential of coupling approved medicinal compounds to usher in novel categories of pharmacological agents, holding promise for addressing a wide spectrum of pathological disorders involving COX-2 and urease enzymes.Communicated by Ramaswamy H. Sarma.

01 Dec 2024·Clinical Pharmacology & Therapeutics

Medications and Acute Hemolysis in G6PD‐Deficient Patients – A Real‐World Study

Article

Author: Gronich, Naomi ; Rosh, Bar ; Saliba, Walid ; Stein, Nili

Many drug labels contain precautions of use in G6PD‐deficient patients due to hemolytic concerns, but much of this is based on scarce clinical, epidemiological, or structural data. In this real‐world study, we aimed to examine if the administration of presumably risky medications for G6PD‐deficient patients was followed by hemolysis. The study is based on data from Clalit Health Services database that provides inclusive health care for more than half of the Israeli population (~ 4.7 million). Within the database, we identified all G6PD‐deficient patients by G6PD <6 U/g Hb. Within the G6PD‐deficient cohort, we identified all hospitalizations with a discharge diagnosis of hemolysis (January 1, 2010 to December 31, 2022), validated the cases, and identified the culprit event. For the rest of the G6PD‐deficient patients with no‐hemolysis, we recorded filled prescriptions of medications listed as presumably risky. We identified 31,962 G6PD‐deficient patients. Within the cohort, there were 71 cases of major hemolysis requiring hospitalization (0.2% of the cohort), of whom 51 (71.8%) had been caused by ingestion of fava beans, six (8.5%) were associated with an infection, and three (4.2%) suggested to be associated with medications (nitrofurantoin, phenazopyridine, and a “pain killer”). Within the 31,875 patients with no major hemolysis, nitrofurantoin has been prescribed safely to 1,366 G6PD‐deficient males and females; hundreds/thousands of G6PD‐deficient patients had been prescribed safely ciprofloxacin, glibenclamide, ofloxacin, phenazopyridine, sulfamethoxazole/cotrimoxazole, sulfasalazine, hydroxychloroquine, glimepiride, mesalazine, and sulfacetamide. In this real‐world study, we are showing that a list of medications, suspected previously as carrying risks for hemolysis in G6PD‐deficient patients, have been prescribed safely to G6PD‐deficient patients, providing reassurance to patients, prescribers, and regulators.

01 Jul 2024·iScience

A high-throughput approach to identify BRCA1-downregulating compounds to enhance PARP inhibitor sensitivity

Article

Author: Salmena, Leonardo ; Narod, Steven A ; Kotsopoulos, Joanne ; Sellars, Erin ; Cancelliere, Sabrina ; Barsyte-Lovejoy, Dalia ; Wu, Jie ; Krishnan, Rehna ; Savguira, Margarita ; Hakem, Anne ; Hakem, Razqallah ; Jen, Mark

PARP inhibitors (PARPi) are efficacious in BRCA1-null tumors; however, their utility is limited in tumors with functional BRCA1. We hypothesized that pharmacologically reducing BRCA1 protein levels could enhance PARPi effectiveness in BRCA1 wild-type tumors. To identify BRCA1 downregulating agents, we generated reporter cell lines using CRISPR-mediated editing to tag endogenous BRCA1 protein with HiBiT. These reporter lines enable the sensitive measurement of BRCA1 protein levels by luminescence. Validated reporter cells were used in a pilot screen of epigenetic-modifying probes and a larger screen of more than 6,000 compounds. We identified 7 compounds that could downregulate BRCA1-HiBiT expression and synergize with olaparib. Three compounds, N-acetyl-N-acetoxy chlorobenzenesulfonamide (NANAC), A-443654, and CHIR-124, were validated to reduce BRCA1 protein levels and sensitize breast cancer cells to the toxic effects of olaparib. These results suggest that BRCA1-HiBiT reporter cells hold promise in developing agents to improve the clinical utility of PARPi.

100 Deals associated with Sulfacetamide Sodium

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KEGG	Wiki	ATC	Drug Bank
D00871	Sulfacetamide Sodium	S01AB04 D10AF06	DB00634

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10 top approved records.

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Indication	Country/Location	Organization	Date
Blepharitis	CN	Jiangsu Shenhua Pharmaceutical Co., Ltd.	29 Apr 2002
Trachoma	CN	Jiangsu Shenhua Pharmaceutical Co., Ltd.	29 Apr 2002
Dermatitis, Seborrheic	US	Bradley Pharmaceuticals, Inc.	24 Mar 2001
Acne Vulgaris	US	Bausch Health US LLC	23 Dec 1996

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