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

Background/Objectives: This study investigates the pharmacological potential of 1,4-dihydropyridine derivatives, functionalized with an imidazo[2,1-b]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 (OB), we explored their repurposing for the treatment of gut motility disorders. Methods: 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 OB 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 Bifidobacterium and Lactobacillus species. Results: Compounds 62 and 65 selectively relaxed intestinal smooth muscle, primarily targeting the longitudinal layer without affecting vascular contractility. Ex vivo testing highlights that compounds 62 and 65 could both modulate gut transit and mixing without causing functional constipation or pain. Microbiota analyses showed no detrimental effects on "good" bacterial species Bifidobacterium and Lactobacillus spp. Conclusions: The favorable gastrointestinal and microbiological profiles of compounds 62 and 65, 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.