Unleashing the potential of vanillic acid: A new twist on nature's recipe to fight inflammation and circumvent azole-resistant fungal infections.

Vanillic acid (VA) - a naturally occurring phenolic compound in plants - is not only used as a flavoring agent but also a prominent metabolite post tea consumption. VA and its associated compounds are believed to play a significant role in preventing diseases, underscoring the need for a systematic investigation. Herein, we report a 4-step synthesis employing the classical organic reactions, such as Willamson's alkylation, Fischer-Spier reaction, and Steglich esterification, complemented with a protection-deprotection strategy to prepare 46 VA derivatives across the five series (1a-1i, 2a-2i, 3, 3a-3i, 4a-4i, 5a-5i) in high yields. The synthesized compounds were investigated for their antifungal, anti-inflammatory, and toxic effects. Notably, compound 1a demonstrated remarkable ROS inhibition with an IC50 value of 5.1 ± 0.7 µg/mL, which is more than twice as effective as the standard ibuprofen drug. A subset of the synthesized derivatives (2b, 2c, 2e, 3b-3d, 4a-4c, 5a, and 5e) manifested their antifungal effect against drug-resistant Candida strains. Compound 5g, in particular, revealed synergism with the established antifungal drugs amphotericin B (AMB) and fluconazole (FLZ), doubling FLZ's potency against azole resistant Candida albican ATCC 36082. Furthermore, 5g improved the potency of these antifungals against FLZ-sensitive strains, including C. glabrata ATCC 2001 and C. parapsilosis ATCC 22019, as well as various multidrug-resistant (MDR) Candida strains, namely C. albicans ATCC 14053, C. albicans CL1, and C. krusei SH2L OM341600. Additionally, pharmacodynamics of compound 5g was examined using time-kill assay, and a benign safety profile was observed with no hemolytic activity in whole blood, and no cytotoxicity towards the normal BJ human cell line. The synergistic potential of 5g was further investigated through both experimental methods and docking simulations.These findings highlight the therapeutic potential of VA derivatives, particularly in addressing inflammation and circumventing FLZ resistance in Candida albicans.

Gastro Oesophageal Reflux Diseases In Chronic Obstructive Pulmonary Disease Patients.

BACKGROUND: There is an association of Gastroesophageal reflux disease (GERD) with chronic obstructive pulmonary disease (COPD). This study was designed to determine the frequency of GERD in COPD patients. METHODS: This descriptive, cross-sectional study was conducted in the Pulmonology Unit Ayub Teaching Hospital Abbottabad. Patients more than 40 years of age of both genders presenting with features of COPD such as cough and breathlessness for more than 6 months and confirmed by spirometry were included in the study. A total of 118 consecutive patients were included in the study. Patients who had spirometry showing FEV1 <70% predicted & FEV1/FVC ratio <70% were included. Patients of asthma, with known oesophageal disease such as cancer, stricture, achalasia or active peptic ulcer disease, Pregnancy (precipitates GERD) and those patients who had used proton pump inhibitors (PPI) in the last 15 days were excluded. RESULTS: The mean age of COPD patients was 65.25 years. Among COPD patients 89 (75.4%) were males. Fifty-five (46.6%) patients had moderate COPD (FEV1:50-69%). Frequency of smokers was 68.6% with mean duration of 12.5years and mean number of cigarettes smoke per day were 13.4. Thirty-five (29.75%) had GERD; 27% in males and 30% in females. CONCLUSIONS: Our study shows that a higher proportion of gastro oesophageal reflux (GERD) symptoms are present in COPD patients and it also shows that GERD is more common in severe COPD patients.