Design, synthesis, biological and computational screening of novel pyridine-based thiadiazole derivatives as prospective anti-inflammatory agents.

In this study, a novel series of pyridine-based thiadiazole derivatives (NTD1-NTD5) were synthesized as prospective anti-inflammatory agents by combining substituted carboxylic acid derivatives of 5-substituted-2-amino-1,3,4-thiadiazole with nicotinoyl isothiocyanate in the presence of acetone. The newly synthesized compounds were characterized by FTIR, 1H NMR, 13C NMR, and mass spectrometry. First, the compounds underwent rigorous in vivo testing for acute toxicity and anti-inflammatory activity and the results revealed that three compounds-NTD1, NTD2, and NTD3, displayed no acute toxicity and significant anti-inflammatory activity, surpassing the efficacy of the standard drug, diclofenac. Notably, NTD3, which featured benzoic acid substitution, emerged as the most potent anti-inflammatory agent among the screened compounds. To further validate these findings, an in silico docking study was carried out against COX-2 bound to diclofenac (PDB ID: 1pxx). The computational analysis demonstrated that NTD2, and NTD3, exhibited substantial binding affinity, with the lowest binding energies (-8.5 and -8.4, kcal/mol) compared to diclofenac (-8.4 kcal/mol). This alignment between in vivo and in silico data supported the robust anti-inflammatory potential of these derivatives. Moreover, molecular dynamics simulations were conducted, extending over 100 ns, to examine the dynamic interactions between the ligands and the target protein. The results solidified NTD3's position as a leading candidate, showing potent inhibitory activity through strong and sustained interactions, including stable hydrogen bond formations. This was further confirmed by RMSD values of 2-2.5 Å and 2-3Ǻ, reinforcing NTD3's potential as a useful anti-inflammatory agent. The drug likeness analysis of NTD3 through SwissADME indicated that most of the predicted parameters including Lipinski rule were within acceptable limits. While these findings are promising, further research is necessary to elucidate the precise relationships between the chemical structures and their activity, as well as to understand the mechanisms underlying their pharmacological effects. This study lays the foundation for the development of novel anti-inflammatory therapeutics, potentially offering improved efficacy and safety profiles.

Identification, Isolation, and Structural Characterization of Novel Forced Degradation Products of Darunavir Using Advanced Analytical Techniques Like UPLC-MS, Prep-HPLC, HRMS, NMR, and FT-IR Spectroscopy.

Since the stability of the pharmaceuticals plays a crucial role in efficacy and safety while using them in the treatment of disorders, the evaluation of purity and impurity profiling of pharmaceuticals is of utmost importance using efficient analytical techniques. The present study explains the identification, isolation, and characterization of stress degradation products of the anti-human immunovirus drug Darunavir. The degradation study was performed to evaluate the stability profile of Darunavir in different stress conditions like hydrolytic, oxidative, thermal, and photolytic conditions as per the ICH guidelines. Degradation products were identified using ultra-performance liquid chromatography coupled with mass spectrometry, isolated using semi-preparative high-performance liquid chromatography, and structural characterization by HRMS and 1H, 13C NMR (1D, 2D). Darunavir is relatively stable in oxidative, thermal, and photolytic conditions; however, considerable degradation was observed in acid and base hydrolysis. A total of five degradation products were identified and isolated in acid and base degradation. DP-1, DP -2, & DP-3 were observed in acid conditions, whereas in base conditions, along with DP-2, two more DPs, i.e., DP-4 & DP-5, were identified. Among the five DPs, two degradation products, namely DP-1: N-(4-(N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylsulfamoyl) phenyl) acetimidamide. & DP-3: hexahydrofuro[2,3-b]furan-3-yl(4-((4-acetimidamido-N-isobutylphenyl)sulfonamido)-3-hydroxy-1-phenylbutan-2-yl)carbamate, are novel, remaining degradation products DP-2: 4-amino-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzenesulfonamide, DP-4: 4-amino-N-(((5S)-4-benzyl-2-oxooxazolidin-5-yl) methyl) -N-isobutyl benzenesulfonamide and DP-5: methyl ((3S)-4-((4-amino-N-isobutylphenyl) sulfonamido)-3-hydroxy-1-phenylbutan-2-yl) carbamate are already reported tentatively using a single analytical technique coupled with mass analysis without any evidence from NMR and IR data. Hence, the present study focused on using High-Resolution Mass, 1D, and 2D 1H, 13C NMR data for concrete confirmation of structures for degradation products. Supplementary Information: The online version contains supplementary material available at 10.1007/s10337-022-04226-z.

Coumarin-chalcone hybrids targeting insulin receptor: Design, synthesis, anti-diabetic activity, and molecular docking.

Four series of thirteen new coumarin-chalcone hybrids (DPCU 1-13, DPCT 1-13, DCCU 1-13 and DCCT 1-13) were designed and synthesized using Biginelli synthesis, Pechmann condensation, Acetylation, and Claisen-Schmidt reactions. Synthesized compounds were tested for insulin receptor in silico docking studies (PDB ID: 1IR3); DCCU 13 and DCCT 13 derivatives received the lowest docking score; Streptozocin (STZ) and Nicotinamide (NA) induced type II diabetes was tested for their anti-diabetic activity in rats. In vivo tests suggested that fasting blood glucose levels of animals treated with DCCU 13 (30 mg/kg body weight) and DCCT 13 (30 mg/kg body weight) were significantly and moderately suppressed, respectively, relative to fasting blood glucose levels of diabetic control animals. Similarly, therapy with DCCU 13 and DCCT 13 attenuated oxidative stress parameters such as lipid peroxidation (MDA), superoxide dismutase (SOD) and increased the glutathione (GSH) in the liver and pancreas in a dose-dependent manner. In comparison, therapy with DCCU 13 (30 mg/kg body weight) mitigated alterations in the histological architecture of the liver and pancreatic tissue. These results indicated that the hybrids DUUC 13 and DCCT 13 at 30 mg/kg had an anti-hyperglycemic and antioxidant impact on STZ + NA mediated type II diabetes in rats. Further detailed work could be required to determine the precise mode of action of the anti-diabetic behavior of hybrids.