Exploring the potential of propanamide-sulfonamide based drug conjugates as dual inhibitors of urease and cyclooxygenase-2: biological and their in silico studies

Abstract

Derivative synthesis has been a crucial method for altering the effects of already-approved medications, especially to lessen adverse effects and enhance results. Making use of this multi-target approach, a series of naproxen-sulfa drug conjugates was designed and synthesized. The newly designed conjugates were confirmed by spectroscopic techniques like IR, 1HNMR, 13CNMR, and elemental analysis. The conjugates were screened for anti-inflammatory, urease, and cyclooxygenase-2 (COX-2) inhibition. Naproxen conjugated with sulfanilamide, sulfathiazole, and sulfaguanidine was found potent and showed a competitive mode of urease inhibition, with IC50 (µM) values 6.69 ± 0.11, 5.82 ± 0.28, 5.06 ± 0.29, respectively. When compared to other screened conjugates, the naproxen-sulfamethoxazole conjugation showed better anti-inflammatory action by inhibiting induced edema by 82.8%, which is comparable to the medication indomethacin (86.8% inhibition). Whereas it exhibited 75.4% inhibition of COX-2 at 10 µM concentration which is comparable with the reference drug (celecoxib, 77.1% inhibition). Moreover, the binding modes of competitive inhibitors with the urease and COX-2 receptor were predicted through molecular docking studies and their stability analysis through MD simulations showed that these compounds made stable complexes with the respective targets and there were no conformational changes that occurred during simulation. The obtained results showed that the conjugates of approved therapeutic molecules may lead to the development of novel types of pharmacological agents in the treatment of several pathological disorders where urease and COX-2 enzymes are involved.

Exploring the Potential of New Benzamide-Acetamide Pharmacophore Containing Sulfonamide as Urease Inhibitors: Structure–Activity Relationship, Kinetics Mechanism, and In Silico Studies

“…It has already been reported that isoxazole substituted on the sulfonamide side and electron-withdrawing groups such as fluoro-substituted biphenyl groups on the acetamide side showed better urease inhibition activities as compared to methyl substituent phenyl groups on the acetamide side. Furthermore, guanidine and amino groups on the sulfonamide side showed excellent urease inhibition activities compared to five- and six-membered heterocyclic substituents. , Overall, the electron-withdrawing and -donating groups attached to phenyl groups play a pivotal role in the inhibition activities of urease enzymes. However, this effect largely depends on the overall structure of the molecule under investigation. , …”

“…Furthermore, guanidine and amino groups on the sulfonamide side showed excellent urease inhibition activities compared to five-and six-membered heterocyclic substituents. 26,27 Overall, the electron-withdrawing and -donating groups attached to phenyl groups play a pivotal role in the inhibition activities of urease enzymes. However, this effect largely depends on the overall structure of the molecule under investigation.…”

“…To prepare safe and secure urease inhibitors, a variety of sulfa drugs and NSAID derivatives have been thoroughly studied in the past decade (Figure ). This research identified a few drug-based conjugates that would be the best pharmacological agents for the inhibition of the urease enzyme. ,, The nonsteroidal anti-inflammatory drugs (NSAIDs) and their derivatives, such as acetylsalicylic acid, ibuprofen, diclofenac, mefenamic acid, flurbiprofen, naproxen, and piroxicam, were investigated for their ability to exhibit a range of biological activities, including inhibiting enzymes like α-glucosidase, β-glucuronidase, α-amylase, and urease. ,,− …”