Nitrogen heterocycles are significantly employed in drug discovery. Numerous pyrido-pyrimidinone scaffolds have a prominent role in therapeutic chemistry because of their broad biological actions. They form a fundamental constituent of various medicinal properties such as anticancer, anti-inflammatory, anti-analgesics, anti-obesity and oxidative burst inhibition properties (Alam, Alsharif, Alkhattabi, Jones, Delancey, Gottsponer & Yang, 2016).The common challenge is finding the most appropriate methods of synthesizing structural variant of pyrido-pyrimidinones. Researchers have made significant strides towards coming up with the less toxic and more environmentally friendly approaches of manufacturing the pyrido-pyrimidinones as demonstrated in this context.
Importance of Nitrogen Heterocyclic Compounds
Heterocyclic compounds are organic compounds with a ring-containing atoms such as oxygen, nitrogen or sulfur forming part of the ring alongside carbon. The rings can either be aromatic and non-aromatic (Dua, Shrivastava, Sonwane & Srivastava, 2011). Heterocyclic compounds are available in the surroundings in abundance and play a central role in the living cells metabolism. In the realm of organic chemistry, heterocyclic chemistry represents a substantial amount of the recent publications and evokes great interest among chemists.
Nitrogen heterocycles are both industrially and biologically relevant. Among the twenty natural amino acids, three of them are heterocyclic (Martins et al., 2015). The application of heterocyclic is quite extensive as they are related with an array of physiological actions. Industrially, a significant quantity of the compounds produced are heterocyclic in nature including agrochemical, pharmaceutical, and veterinary products (Dua, Shrivastava, Sonwane & Srivastava, 2011). Synthetic Nitrogen heterocycles are used as a rocket propellant and also in photography.
Heterocyclics have the ability to react in an extraordinary way. They can either act as acids or alkalines depending on the PH to produce either anions or cations (Dua, Shrivastava, Sonwane & Srivastava, 2011). There are some that react with nucleophilic substances, others with electrophilic agents yet some react with both. There are some which cannot be reduced yet are readily oxidized and some are stable in oxidizing agents but readily hydrogenated. Heterocyclics also have great ability to produce stable complexes with metal ions which give them a big significance biochemically.
There are a significant amount of heterocyclic compounds that are pharmacologically active and have therapeutic use. Some are natural products including penicillin, morphine, cardiac glycosides, vinblastine, and cephalosporins (Dua, Shrivastava, Sonwane & Srivastava, 2011). Synthetic heterocyclics also represent a noteworthy number and are widely used as anticancer agents, antidepressants, analgesics, hypnotics and analeptics. Other heterocyclic compounds are used as insecticides, pesticides, rodenticides and weedicides.
Nitrogen heterocycles are such an essential group of heterocyclic compounds and has significantly contributed in the therapeutic chemistry domain. These compounds are classified depending on the position and the number of nitrogen atoms in the ring. For instance, Pyrimidine has a single nitrogen atom in the ring while diazine and pyrazine have two nitrogen atoms. Examples of saturated nitrogen heterocycles include pyrroles, pyrazines, pyridines, 1, 2, 3-triazoles, imidazoles, and 1, 2, 4-triazines. Several nitrogen-containing heterocyclic building blocks are used in agriculture science, pharmaceutical research and drug discovery (Gupta, 2015). Nitrogen heterocycles are the most useful among all heterocycles since most of them show better biological activity compared to the non-nitrogen ones.
Uses of Nitrogen Heterocycles
Antibiotics are the most prescribed medicines in contemporary medicine. Ideally, their utility is to injure or kill bacteria. Antibiotics are part of the antimicrobial compounds family which are used in the treatment of microorganism causing infections such as protozoa and fungi. Some antibiotics such as aminoglycosides are isolated from living organisms (Dua, Shrivastava, Sonwane & Srivastava, 2011). Nitrogen heterocycles such as pyrimidine exhibit antibacterial charecteristics and some of the medications in the market include Metiotrim and Tetroxoprim.
As antiemetic agents
Nitrogen heterocycles have been used for the treatment of nausea and vomiting usually caused by cancer chemotherapy and other side effects experienced after treatment. Several nitrogen heterocycles have shown to have 5-HT3 receptor affinity.
The anti-migraine substances mimic the activity of natural 5-HT neurotransmitter, serotonin. 5- (tetrwol-5-methyl)-3-(2-aminoethyl) indole is the active anti-migraine compound found in Nitrogen heterocycles.
As anti-ulcer agents
The pyridine has a primary role in human metabolism since it interacts with amino acids. The effective medications presently available have pyridine moiety.
As anti-inflammatories and analgesics such as Afloqualone, epirizole,celecoxib compounds.
As anti-cancer with compounds such as Nilotinib, Dasatinib, Bosutinib, and Trimethoprim.
As anti-fungal for example, Flucytosine.
As anti-viral such as Broxuridine and Idoxuridina,
Most of the synthetic Nitrogen heterocycles are also being used as anticancer, antimicrobials, hypnotics, analgesics, rodenticides and pesticides (Dua, Shrivastava, Sonwane & Srivastava, 2011). Other synthetic heterocycles also have practical applications including as solvents, dyestuffs, photographic sensitizers, antioxidants, developers as well as in rubber industry as vulcanization accelerators.
Importance of nitrogen heterocyclic compounds in pharmaceutical research
The biological significance and structural diversity of nitrogen containing heterocycles have interested so many researchers making the synthesis of these substances a big target (Martins et al., 2015). Ideally, they are readily available in natural products and are regarded as products of biological and chemical importance. The study of Nitrogen heterocycles is very extensive and have been utilized in the synthesis of most alkaloids. They are precursors to numerous biologically potent compounds which makes the scientific machinery to focus on how to harness this functionality (Martins et al., 2015). Alongside their derivatives, Nitrogen heterocycles synthesis form an essential part in the synthetic and natural organic chemistry domain because of their pharmacological and therapeutic properties.
The Nitrogen heterocycles have appeared as essential pillars of more than seven thousand currently existing drugs (Gupta, 2015). Additionally, they are superlative frameworks for creating libraries of medicine-like compounds as well as to generate the HIV-1 protease inhibitors library. Most of the building blocks of nitrogen heterocycles have been used severally in drug discovery as well as pharmaceutical research. Nitrogen heterocycles have the capability of manifesting substituents around a central scaffold in clear 3-D exemplifications, a feature that most researchers have exploited to the drug discovery advantage.
In the modern drug design, heterocyclic serve as essential tools to manipulate polarity, lipophilicity and the capacity for hydrogen bonding which may result in enhanced pharmacokinetics, pharmacological, physicochemical and toxicological properties of ultimately and candidate drugs (Gupta, 2015). The heterocycles nucleus forms the integral feature of numerous medicinal agents and natural products. It is a vital structural component of very many drug categories including analgesics, antimicrobial, anti-inflammatory, antiviral, analgesic, antihistaminic, antitubercular, immunomodulatory, antiobesity and antidiabetic agents. Heterocycles have a significant role in thebiochemical process because DNA and RNA (the side group of most common and crucial constituents of living organisms) are based on aromatic heterocycles (Martins et al., 2015). Nitrogen heterocycles have facilitated the pharmaceutical research because of their unique structures and biological activities.
Different Synthesis of Pyridopyrimidinone
Pyridopyrimidinone and its derivatives have been studied due to a variety of biological and chemical significance. There are several methods developed for the synthesis of the pyridopyrimidines including:
Synthesis of pyridopyrimidinone derivatives containing thiophene ring.
As determined by Raju, Naveen, Chandana and Nadendla (2016), thiophene is a paramount class of heterocyclic compound with significant pharmacological and biological activities such as anti-inflammatory, anticancer, antimicrobial and antioxidant. In their study, they synthesized 2-Methyl-5-thiophen-7-(aryl-2-yl) pyrido [2,3-d] pyrimidin-4(3H)-one derivatives from 2-methyl-4-aryl-6-(thiophen-2-yl) pyridine-3-carbonitrile (0.01mol) and 20ml acetic acid with concentrated sulphuric acid acting as a catalyst. The mixture was left to cool at room temperature before pouring it into cold water. The solid was obtained by filtration, cleaned in 20mls of chloroform before using methanol to crystalizing the crude product to form the analytical pure compound.
Synthesis of 2, 3-dihydro-4H-pyrido [1, 2-a] pyrimidin-4-ones
Alam et al. (2016), acknowledge that different pyrido-pyrimidinone scaffolds have a vital spot in the therapeutic chemistry because of their exceptional biological actions. It forms a vital component of several natural products having an array of therapeutic characteristics including anti-influenza, anti-obesity, anti-tumor, lipid droplet synthesis inhibition and oxidative burst inhibition properties. These nitrogenous bicyclics are also used in the production of drugs for cancer, depression, asthma, neurological disorders, and hypertension. In their research dihydroprimo-pyrimidinone was synthesized from a mixture of 1mmol of 2-aminopyridine and 1.1 mmol of methyl acrylate in 1mk of HFIP. It was refluxed or stirred for a certain period. TLC observed the progress of the chemical reaction. When the reaction was complete, the product was obtained from filtration of the solvent. Evaporation was used to get the product from the homogenous reaction mixture.
Synthesis of pyridopyrimidine derivatives from 2-amino-4, 6-bis (4-chlophynyl) nicotinonitrile
According to El-shat, Elhefny, El-Sayed and Salama (2015), 2-amino-4, 6-bis (4-chlorophenyl) nicotinonitrile is potent with high pharmacological activities. The researchers state that the fused pyridopyrimidine derivatives have a vital role in biochemical processes due to the side groups of the most essential and ordinary components of living cell RNA and DNA are founded on aromatic heterocycles. Some of their pharmacological activities include tuberculostatic, CNS depressant, anticancer agent, antiinflammatory and analgesic activity. 2-amono-4, 6-bis (4-chlorophenyl) nicotinonitrile was a vital compound in this study regarding the syntheses of the fused heterocyles. Pyrodo-[2, 3-d] pyrimidin-4-one derivative was achieved by refluxing 2-amino-4, 6-bis94-chlorophenyl) nicotinonitrile with formic acid. For 5, 7- Bis (4-cholorophynyl) pyrido [2, 3-d] was heated for three hours under reflux. The mixture was then left at room temperature to cool before pouring in 50ml of cold water. Filtration was used to obtain the solid which was purified by recrystallization. The next fused derivatives have been achieved from the previous products.
Synthesis of 2-aminopyridopyriminidonone bases c-Jun N-Terminal Kinase (JNK) inhibitors
Zheng et al. (2015), point out that recent studies have shown that JKN1 and JKN2 play a significant role in the advancement of hear...
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