In this study, two series of small molecules as enzyme inhibitors were designed and synthesized. The first series is imidazo[2,1-b]thiazole derivatives as potential urease inhibitors whereas the second series is quinolines as C-RAF kinase inhibitors. In the first part of the present work, the urease was targeted by a new series of sulfonates and sulfamates bearing an imidazo[2,1-b]thiazole scaffold. Interestingly, all derivatives exhibited a potent inhibitory activity of urease enzyme in sub-millimolar range. The most potent compound, 2c inhibited urease with an IC50 value of 2.94 ± 0.05 μM, which is 8-fold more potent than the thiourea positive control (IC50 = 22.3 ± 0.031 μM). Molecular modeling studies of the most potent inhibitors in the urease active site suggested multiple binding interactions with distinct amino acid residues. Phenotypic screening of the developed compounds against Helicobacter. pylori (H. pylori) delivered molecules that possess high potency (1a, 1d, 1h, 2d, and 2f) in comparison to the reference compound, acetohydroxamic acid. Further studies were conducted to investigate the selectivity of these compounds against AGS gastric cell line and Escherichia coli (E. coli). Permeability of the most promising derivatives (1a, 1d, 1h, 2d, and 2f) in Caco-2 cell line was investigated. As a result, compound 1d present itself as a lead drug candidate since it exhibited a promising inhibition against urease with an IC50 of 3.09 ± 0.07 μM, MIC (Minimum inhibitory concentration) value against H. pylori of 0.031 ± 0.011 mM, and selectivity index (SI) against AGS of 6.05. Interestingly, compound 1d lacked activity against urease-negative E. coli and exhibited a low permeability in Caco-2 cells which supports the potential use of this compound for Gastrointestinal Tract (GIT) infection with minimal systemic effect(s). In the second series, we introduced new diarylurea and diarylamide derivatives including those bearing a quinoline core, armed with various functio