Design and Synthesis of Anti-Viral and Cardio-Vascular Remedies
Design and Synthesis of Compounds Possessing of Anti-Viral (Anti-HIV) Action and/or Regulating the Activity of Cardio-Vascular System
Tech Area / Field
- MED-DRG/Drug Discovery/Medicine
- CHE-SYN/Basic and Synthetic Chemistry/Chemistry
8 Project completed
Senior Project Manager
Melnikov V G
Scientific Technological Centre of Organic and Pharmaceutical Chemistry SNPO / Institute of Fine Organic Chemistry, Armenia, Yerevan
- Universidad de Navarra, Spain, Pamplona\nKatholieke Universiteit Leuven / Rega Institute for Medical research, Belgium, Leuven\nUniversité d'Orléans / Institut de Chimie Organique et Analytique, France, Orleans\nUniversité de Poitiers, France, Poitiers\nRheinischen Friedrich-Wilhelms-Universitat Bonn / Kekule-Institut fur Organische Chemie und Biochemie, Germany, Bonn\nUniversity of Murcia / Synthetic Organic Chemistry Group, Spain, Murcia\nCardiff University, UK, Cardiff\nUniversitat Regensburg / Institut fur Organische Chemie, Germany, Regensburg
Project summaryThe modern medicine has reached high results in treatment of the majority of diseases due to successes in creation of effective synthetic medicines. In spite of now drug therapy is the most productive means in treatment of different diseases none the less the problem of selectively acting drugs using for treatment of cardio-vascular and viral diseases stays strongly actual, because of mortality and losses of capacity for work causing by these diseases are of extremely high level and have tendency for increase.
The ways for regulation of cardio-vascular system activity are various. Particularly this is the regulation over - and adrenoblockers, cholinoreceptors, influence on ionic current (Ca2+, Na+, K+), immediate action on vessels and cardio activity, enzyme system, etc. Naturally, the spectrum of chemical structures, acting on the cardio-vascular system is also wide.
The spectrum of viral diseases is broad as well, including partially Acquired Immuno-Deficit Syndrome (AIDS). Nucleoside derivatives and their modified acyclic analogues, which have block HIV reproduction in cells, as well as non-nucleoside heterocyclic inhibitors of reverse-transcriptase or so called «butterfly»-like compounds, which have directly block reverse-transcriptase and, recently, integrase-blocking substances are used for this purpose.
For optimization of quantity compounds to be synthesized and creation of conditions for estimation structure – activity correlation as well as for choosing of most active compounds for preclinical investigation as pro-drugs the working hypothesis has been suggested by us for searching of biologically active substances on the base of our own investigations and literary material.
The key basis of this hypothesis is genetic and/or structural correlation between different heterocyclic compounds and arylalkylamines. Such approach has justified itself earlier and as result series of highly efficient compounds have been obtained under the following conditional designations: ETAPHOLOL, DIFALKYN, AMYCHRON, FOBUPHOL, BEDITINE, MESEDINE, IFOC No.7071, etc.
Proceeding from above-stated, we suggest to realize a Project on synthesis of substances, regulating cardio-vascular system activity or possessing of antiviral action. Such approach will secure the solving of one of most fundamental problem in this field – estimation of structure – biological action correlation.
General structure of the suggested Project is given in the Scheme below.
The works on the Project consist of three basic parts. The first – fundamental part (fragment A) is isoquinoline derivative, substituted in 1, 2, 4, 6, 7 positions, the main versions of obtaining of which have been working out by us. Especially important significance has lipophile spiro-cycloalkane substituents X in the fourth position.
By means epichlorhydrine of interaction of isoquinoline derivatives of halogenderivatives of aliphatic acids (C2-C5) with epichlorhydrine or aliphatic dihalogenderivatives the structural fragment A is synthesized, consisting from two parts – heterocyclic and aliphatic. This fragment contains different functional groups (-OH, -Cl or -Br, -COOR). Connecting different amines (aliphatic, aromatic or heterocyclic) by these functional groups, we obtain series of goal biologically active compounds.
Generalizing above-stated conclusions the general construction of substances which will be synthesized can be presented as follows:
The selectivity of action is achieved by combination of these three fragments. So, when S1-type substituents present an action on adrenoreceptors (cardio-vascular action) is reached. S2-type substituents stipulate for antiarrhythmic action, in the same time S3- and S4-type substituents causes, mainly, antiviral activity.
Thus, it turned out well to obtain efficient compounds, acting in two main directions – regulation of cardio-vascular activity or antiviral action, as well to study structure – action correlation and choose most active compounds for preclinical investigations using the single scheme for synthesis.
It is supposed to select for clinical investigations (as pro-drugs) 3-5 new compounds.
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