Background/Objectives: SARS-CoV-2 is one of the viruses that caused worldwide health issues. This effect is mainly due to the wide range of disease prognoses it can cause. The aim of this study is to determine protein profiles that can be used as potential biomarkers for patients’ stratification, as well as potential targets for drug development. Methods: Eighty peripheral blood samples were collected from heathy as well as SARS-CoV-2 patients admitted at a major tertiary care center in Riyadh, Saudi Arabia. A label-free quantitative mass spectrometry-based proteomic analysis was conducted on the extracted sera. Protein–protein interactions and functional annotations of identified proteins were performed using the STRING. Results: In total, two-hundred-eighty-eight proteins were dysregulated among all four categories. Dysregulated proteins were mainly involved in the network map of SARS-CoV-2, immune responses, complement activation, and lipid transport. Compared to healthy subjects, the most common upregulated protein in all three categories were CRP, LGALS3BP, SAA2, as well as others involved in SARS-CoV-2 pathways such as ZAP70 and IGLL1. Notably, we found fifteen proteins that significantly discriminate between healthy/recovered subjects and moderate/under medication patients, among which are the SERPINA7, HSPD1 and TTC41P proteins. These proteins were also significantly downregulated in under medication versus moderate patients. Conclusions: Our results emphasize the possible association of specific proteins with the SARS-CoV-2 pathogenesis and their potential use as disease biomarkers and drug targets. Our study also gave insights about specific proteins that are likely increased upon infection but are likely restored post recovery.

New pyrazolyl sulfonamide conjugates 5 , 6 , and 7 were synthesized by reacting N‐(4‐(hydrazinecarbonyl) aryl) benzenesulfonamide with acetyl acetone, ethyl acetoacetate, and/or 2‐(ethoxymethylene)malononitrile. The DFT computations of the constructed derivatives exhibited comparable bent shapes. The conjugates 5a‐b and 6a‐b displayed parallel HOMO‐LUMO structures, whereas the nitro‐derivatives 5c and 6c exhibited alternative configurations of their FMOs. Furthermore, the antimicrobial activity was assessed against different bacterial and fungal pathogens. Pyrazole derivatives 5c , 6b , 7a , and 7c exhibited high activity against S. aureus (MIC = 3.125–6.25 μg/mL) and E. coli (MIC = 3.125 μg/mL), exceeding the activity of standard antibiotics, with 6b demonstrating the broadest spectrum of activity against both bacteria and fungi. The in vitro DHFR inhibitory effects of the investigated sulfonamides were examined and compared with those of methotrexate. Among the screened derivatives, hybrids 7a‐c displayed more potent inhibitory activities, thereby determining the effect of substitution patterns on activity. Additionally, the molecular docking of the manufactured analogs against the dihydrofolate reductase enzyme (PDB: 3TZF) was investigated, where hybrid 6a exhibited the highest activity with a binding score ( S = −6.5129 kcal/mol), which was greater than that of methotrexate ( S = −6.4743 kcal/mol). Moreover, pharmacokinetic characteristics were simulated using SwissADME to evaluate drug‐likeness and potential oral bioavailability. All hybrids exhibited beneficial physicochemical properties within acceptable drug‐likeness limits, confirming the pyrazole‐sulfonamide scaffold as an optimization target for future orally active drug candidates with good pharmacokinetic potential.