Design, Synthesis and Calcium Channel Blocking Activity of Diltiazem- Verapamil Hybrid MoleculesAhmed S Mehanna1*, Timothy J Maher1 and Pintapa P Grongsaard2
- *Corresponding Author:
- Ahmed Mehanna
Professor of Medicinal Chemistry
Department of Pharmaceutical Sciences
School of Pharmacy-Boston
179 Longwood Avenue
Boston MA 02115, USA
E-mail: [email protected]
Received date: August 20, 2014; Accepted date: September 25, 2014; Published date: September 27, 2014
Citation: Mehanna AS, Maher TJ, Grongsaard PP (2014) Design, Synthesis and Calcium Channel Blocking Activity of Diltiazem-Verapamil Hybrid Molecules. Med chem 4:704-703. doi: 10.4172/2161-0444.1000216
Copyright: 2014 Mehanna AS, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The current manuscript describes the design, synthesis, and in vitro testing of four thioacetanilides with diltiazemverapamil hybrid structural features as potential calcium channel blockers. The current hybrid strategy of drug design aimed to generate compounds that could span, with a single compound, the trans-membrane locales where the two drugs bind, with the ultimate goal of increasing the blocking activity. The latter, was assessed by measuring the inhibitory effects, expressed as IC50, on calcium-induced contractions of potassium depolarized isolated rat aorta strips. The assessment of the binding locales was determined by incubating the test compound with aortic strips for two different periods, 10-minutes and 2-hours, before adding the contractile calcium ions to the assay medium. Diltiazem IC50 values were 0.26 and 0.14 μM, after 10-minutes and 2-hours, respectively, reflecting less than two fold increase in activity and confirming previous reports that its locale of binding in mostly on the exterior side of the membrane. On the other hand, verapamil IC50 values were 0.47 and 0.14 μM after 10-minutes and 2-hour incubation respectively, reflecting approximately a 3-4 fold increase in activity and confirming previous reports that it binds mainly to the interior domains of the membrane. The four designed hybrid compounds showed, after 10-minute incubation, an IC50 value range of 3.7-12.0 μM, and after 2-hour incubation an IC50 range of 0.78-2.12 μM, reflecting approximately a 5-fold increase in activity suggesting more similarity to the verapamil binding profile. The data indicate that the designed compounds are with moderate activities, but generally less active as calcium channel blockers than either of the two parent drugs.