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Computer--based drug design, synthesis and biological evaluation of new pyrimidinone derivatives linked to arylpiperazine and 2'-carbethoxy-biphenylylmethyl moeities as alpha1-adrenoceptor antagonists and angiotensin II AT1 receptor antagonists. 2010

M A H Ismail, and D A Abou El Ella, and K A M Abouzid, and G H A Al-Ansary
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbasseya, Cairo, Egypt. mhismaeel@yahoo.com

Two new series of pyrimidinone derivatives linked to arylpiperazine moieties and 2'-carbethoxy-biphenylmethyl moieties were designed, synthesized and biologically evaluated for their in vivo hypotensive activities. The design of arylpiperazine analogues (IIa-f, IIIa-c, VIIa.b, IX) was based upon structural modification of the newly discovered selective alpha1-AR antagonist drug; Urapidil. Compare/fit studies of these molecules with the previously generated and validated alpha1-AR antagonist hypothesis showed that these molecules have comparable affinities for the alpha1-AR antagonist hypothesis while compound IIIc had the highest fitting value. The in vivo biological evaluation of these compounds for their effects on blood pressure of normotensive cats in comparison to the lead compound prazosin, was consistent with the results of molecular modeling fit values. As expected, compound IIIc exhibited the highest hypotensive activity among the test set compounds. Meanwhile, the design of 2'-carbethoxy-biphenylylmethyl analogues (XIa,b) was based upon the molecular modeling simulation fitting of their carboxylic acid bioprecursors with the previously generated and validated Ang II receptor antagonist hypothesis. Such compare/fit studies predicted that the designed compounds (XIa,b) showed comparable fitting affinities between their de-esterified analogues and the Ang II antagonist pharmacophore. In vivo biological evaluation of these compounds for their effects on blood pressure of normotensive cats showed that compound Xla exhibited hypotensive activity more or less similar to losartan.

UI MeSH Term Description Entries
D007202 Indicators and Reagents Substances used for the detection, identification, analysis, etc. of chemical, biological, or pathologic processes or conditions. Indicators are substances that change in physical appearance, e.g., color, at or approaching the endpoint of a chemical titration, e.g., on the passage between acidity and alkalinity. Reagents are substances used for the detection or determination of another substance by chemical or microscopical means, especially analysis. Types of reagents are precipitants, solvents, oxidizers, reducers, fluxes, and colorimetric reagents. (From Grant & Hackh's Chemical Dictionary, 5th ed, p301, p499) Indicator,Reagent,Reagents,Indicators,Reagents and Indicators
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D010879 Piperazines Compounds that are derived from PIPERAZINE.
D011487 Protein Conformation The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). Conformation, Protein,Conformations, Protein,Protein Conformations
D011743 Pyrimidines A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.
D011744 Pyrimidinones Heterocyclic compounds known as 2-pyrimidones (or 2-hydroxypyrimidines) and 4-pyrimidones (or 4-hydroxypyrimidines) with the general formula C4H4N2O. Pyrimidinone,Pyrimidone,Pyrimidones
D001794 Blood Pressure PRESSURE of the BLOOD on the ARTERIES and other BLOOD VESSELS. Systolic Pressure,Diastolic Pressure,Pulse Pressure,Pressure, Blood,Pressure, Diastolic,Pressure, Pulse,Pressure, Systolic,Pressures, Systolic
D003198 Computer Simulation Computer-based representation of physical systems and phenomena such as chemical processes. Computational Modeling,Computational Modelling,Computer Models,In silico Modeling,In silico Models,In silico Simulation,Models, Computer,Computerized Models,Computer Model,Computer Simulations,Computerized Model,In silico Model,Model, Computer,Model, Computerized,Model, In silico,Modeling, Computational,Modeling, In silico,Modelling, Computational,Simulation, Computer,Simulation, In silico,Simulations, Computer
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001713 Biphenyl Compounds Whitish aromatic crystalline organic compounds made up of two conjoined BENZENE rings. Compounds, Biphenyl

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