Theoretical ab initio study of ranitidine

Abstract

ABSTRACT:The presence of a heterocyclic ring containing a basic center linked via a methylene chain to a substituted guanidine or thiourea polar side chain, such as found in the H2-antagonist metiamide, which has an imidazole heterocyclic ring, has often been identified as one of the requirements for H2-antagonist activity. In ranitidine, on the other hand, the imidazole ring is substituted for a furan ring, yielding a more active biological H2 antagonist. In this work, we have used the ab initio Hartree-Fock (HF) and second-order Møller-Plesset (MP2) methods in order to investigate the open and folded ranitidine conformations, of the type observed in metiamide. Five basis sets (3-21G, 3-21+G * * , 6-31G, 6-31+G * * , and 6-31+G * * ) were used in order to obtain fully optimized geometric parameters that indicated good agreement with the experimental crystallographic data. We have also investigated in this work the effects of solvents in both ranitidine and metiamide. Monocationic ranitidine was also investigated. All our results, indicate that, as in metiamide, the folded conformation is also preferred. We have investigated Mulliken and natural bond order (NBO) charge distributions, electrostatic and hydrogen bond effects on stabilizing the conformations and discussed the interactions of ranitidine with the biological receptor.

A theoretical and spectroscopic study of carbamazepine polymorphs

“…24 -29 . Ranitidine hydrochloride has been investigated in relation to crystallographic data, 30 but the authors are unaware of any other studies involving drug polymorphism and prediction of the vibrational spectra of drug polymorphs.…”

“…This may be contrasted with the flexible structure of other drugs, such as ranitidine, where the polymorphs are structurally more different. Martins et al, 30 in a comprehensive study of the different forms of ranitidine (folded versus open structure), demonstrated that the prediction of H-bonded species was sensitive to basis set and method; however, many of the other structural properties, bond lengths and angles were much less dependent on the level of basis set or methods used. The structure of carbamazepine may be readily predicted by ab initio calculation, but we have found that the prediction of vibrational spectroscopic properties is rather dependent on the computational method used, particularly in systems were there exists extensive -electron conjugation, as is the case in carbamazepine.…”

A computational study of intramolecular hydrogen bonds breaking/formation: impact on the structural flexibility of the ranitidine molecule

“…The bonding pattern of the structure A, obtained in the DFT calculations, reminds of the one predicted using the MP2 method. The energy difference between the folded and open structures calculated from the MP2 method with polarization and diffuse functions (6-31+G * * ) is 41.05 kJ mol −1 [28]. The corresponding energy differences for the DFT method utilizing the localized orbitals and PW approach are 69.69 and 48.09 kJ mol −1 , respectively.…”

“…We performed static DFT calculations to obtain global and local minima of the ranitidine molecule, which were used as the starting configurations for the analysis of the molecular [28]. Since the RNT molecule is very flexible and has many degrees of freedom (see Fig.…”

“…Furthermore, the possibility of the intramolecular hydrogen bonds formation and its dynamics at finite temperature can be also shown. The structural properties of the opened and folded ranitidine conformations, a RNT monocationic form, and the effects of solvent were investigated by Martins et al utilizing Hartree-Fock and second-order Møller-Plesset methods [28]. The geometry of the ranitidine molecule is mainly determined by the hydrogen bonds, namely N-H· · · O, N-H· · · N, C-H· · · O, C-H· · · N and N-H· · · S, which are responsible for changing the stiffness of the molecules [8,20].…”