Repurposing 1,4-Dihydropyridine Scaffold: 4-Imidazo[2,1-b]thiazole-Derivatives from Calcium Entry Blockers to a New Approach for Gut Dysfunctional Motility

<b>Background/Objectives</b>: This study investigates the pharmacological potential of 1,4-dihydropyridine derivatives, functionalized with an imidazo[2,1-<i>b</i>]thiazole scaffold, as selective modulators of intestinal motility. Given their structural similarity to both L-type calcium channel blockers and spasmolytics such as Otilonium Bromide (<b>OB</b>), we explored their repurposing for the treatment of gut motility disorders. <b>Methods</b>: A focused library of 83 1,4-dihydropyridine derivatives was screened for spasmolytic activity on potassium (80 mM)-induced depolarization in isolated guinea pig ileal and colonic tissues. Compounds showing pharmacodynamic profiles similar to <b>OB</b> and nifedipine were further evaluated for their effects on the spontaneous contractility of longitudinal and circular smooth muscle layers. Additional functional assays assessed intestinal transit, visceral nociception, and mixing/fragmentation efficiency. Microbiota safety was preliminarily tested on mixed cultures of <i>Bifidobacterium</i> and <i>Lactobacillus</i> species. <b>Results</b>: Compounds <b>62</b> and <b>65</b> selectively relaxed intestinal smooth muscle, primarily targeting the longitudinal layer without affecting vascular contractility. Ex vivo testing highlights that compounds <b>62</b> and <b>65</b> could both modulate gut transit and mixing without causing functional constipation or pain. Microbiota analyses showed no detrimental effects on "good" bacterial species <i>Bifidobacterium</i> and <i>Lactobacillus</i> spp. <b>Conclusions</b>: The favorable gastrointestinal and microbiological profiles of compounds <b>62</b> and <b>65</b>, combined with their structural versatility, support their potential repurposing for functional bowel disorders. Their selective activity suggests a promising role in therapies targeting intestinal motility while preserving microbiota homeostasis, supporting the need for extended pharmacological characterization.