An Effort To Understand the Molecular Basis of Hypertension through the Study of Conformational Analysis of Losartan and Sarmesin Using a Combination of Nuclear Magnetic Resonance Spectroscopy and Theoretical Calculations

Abstract

Losartan is the first recently approved drug against hypertension disease that competes with the biological action of angiotensin II (AII) at the AT1 receptor. Its design was based on the mimicry of the C-terminal segment of AII. Due to the biological significance of Losartan, its structure elucidation and conformational properties are reported as determined by NMR spectroscopy and computational analysis. In addition, molecular modeling of the peptide Sarmesin [Sar1Tyr(OMe)4AII], a competitive antagonist of AII, was also developed based on NMR and computational analysis data. Sarmesin's C-terminal was used as a template for superimposition with specific molecular features of interest in the structure of Losartan such as the conformation of biphenyltetrazole, the n-butyl chain, and the orientation of hydroxymethylimidazole relative to the biphenyl template. The major conclusions derived from this study are the following: (a) Sarmesin, like the AII superagonist [Sar1]AII, adopts a conformation which keeps in close proximity the key amino acids Sar1 (or Arg2)-Tyr(OMe)4-His6-Phe8. (b) Losartan favors a low-energy conformation in which imidazole and tetrazole rings are placed in the opposite site relative to the spacer phenyl ring plane; the hydroxymethyl group is placed away from the spacer phenyl ring, the alkyl chain is oriented above the spacer phenyl ring, and the two phenyl rings deviate approximately 60 degrees from being coplanar. (c) Overlay of the C-terminal region of Sarmesin with Losartan using equivalent groups revealed an excellent match. (d) Interestingly, the matching between enantiomeric structures of Losartan was not equivalent, proposing that the chirality of this molecule is significant in order to exert its biological activity. These findings open a new avenue for synthetic chemists to design and synthesize peptidomimetic drugs based on the C-terminal segment of the proposed model of Sarmesin. The new candidate drug molecules are not restricted to structurally resemble Losartan as the design is hitherto focused.

Molecular Structure, Vibrational Spectra and Photochemistry of 2-Methyl-2H-Tetrazol-5-Amine in Solid Argon

“…On the other hand, the two conformers of 3-methyl-1H-tetrazol-3-ium-5-aminide differ in energy by 17.2 kJ mol -1 , because in conformer A the repulsion between the aminide and tetrazole-ring hydrogen atoms is absent. The imine tautomer exhibits both NH and NCH 3 . For this tautomer, the relative energies of the two conformers were also found to be influenced by the presence (in the less stable conformer A) or absence (in the more stable conformer B) of the repulsion between the imine and tetrazole-ring hydrogen atoms.…”

Tautomer Selective Photochemistry in 1-(Tetrazol-5-yl)ethanol

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] From a fundamental point of view, tetrazoles are also particularly interesting systems, especially because of the tautomerism they may exhibit and their diversified photochemistry. 1,[21][22][23][24][25][26][27][28][29] Unsubstituted tetrazole, for example, was found to exist exclusively in the crystalline phases as the 1H-tautomer, [30][31][32] whereas in solution and gas phase 1H-and 2H-tautomers coexist, the population of the most polar 1H form increasing with the polarity of the solvent.…”

Rational design, efficient syntheses and biological evaluation of N , N ′-symmetrically bis-substituted butylimidazole analogs as a new class of potent Angiotensin II receptor blockers

“…The doublet resonating at 6.86 ppm and assigned to 12 0 and 16 0 protons is correlated through coupling with the doublet at 7.04 ppm. Such correlation is evident also with Losartan molecule that contains biphenyltetrazole segment [32]. As the integration of the doublet shows the existence of three protons, the other one is assigned to H18 0 .…”

“…The two different patterns of biphenyl rings are observed in our previous studies using commercial and synthetic ARBs. In Losartan [32], Valsartan [33] and Eprosartan [34] the A ring shows clearly the doublet of doublet pattern common for 1,4 bis-substituted aromatic compounds. However, in the synthetic analog V8 a singlet peak is observed that is attributed to the same ring [17,35].…”