Abatement of Forskolin-induced Intestinal Fluid Secretion by Modulation of Intracellular Camp With Penicillin

Millions of people die every year due to diarrheal related diseases, with infants and the elderly making up the majority of these deaths. Deaths are caused by excessive intestinal fluid and electrolyte secretion and are especially common in impoverished developing countries. Antibiotics have been classically used as a method to treat diarrhea-related pathologies by modulating the gut microbiome. We recently reported that penicillin may protect against disease-induced excessive fluid and electrolyte secretion via a genetics-independent, microbiome-independent mechanism in individual colonic crypt cells. In this study we investigated whether microbial-independent protective effects of penicillin against fluid secretion can be observed in the rat small intestine at the whole-tissue level. Here we report that penicillin has a significant dose-dependent protective effect against fluid secretion in induced models of diarrhea in the microbiome deficient rat small intestine. Penicillin can rapidly bring fluid secretion down to levels comparable to healthy controls. Our results suggest, for the first time, an alternative function for penicillin G as a cost-effective and fast-acting treatment against diarrheal symptoms without dependence on modulating the behavior of the existing gut microbiome.

Design, synthesis, molecular docking, and in vitro α-glucosidase inhibitory activities of novel 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines against yeast and rat α-glucosidase

In an attempt to find novel, potent α-glucosidase inhibitors, a library of poly-substituted 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines 3a–ag have been synthesized through heating a mixture of 2-aminobenzimidazoles 1 and α-azidochalcone 2 under the mild conditions. This efficient, facile protocol has been resulted into the desirable compounds with a wide substrate scope in good to excellent yields. Afterwards, their inhibitory activities against yeast α-glucosidase enzyme were investigated. Showing IC50 values ranging from 16.4 ± 0.36 µM to 297.0 ± 1.2 µM confirmed their excellent potency to inhibit α-glucosidase which encouraged us to perform further studies on α-glucosidase enzymes obtained from rat as a mammal source. Among various synthesized 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines, compound 3k exhibited the highest potency against both Saccharomyces cerevisiae α-glucosidase (IC50 = 16.4 ± 0.36 μM) and rat small intestine α-glucosidase (IC50 = 45.0 ± 8.2 μM). Moreover, the role of amine moiety on the observed activity was studied through substituting with chlorine and hydrogen resulted into a considerable deterioration on the inhibitory activity. Kinetic study and molecular docking study have confirmed the in-vitro results.