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Quinzoline Drugs Essay

2262 words - 10 pages

Anti-HIV: Viruses are difficult targets for selective treatment because they rely largely on the host cell’s metabolic activities for their replication. Most antiviral agents inhibit viral un-coating, interfere with viral nucleic acid synthesis, or prevent the assembly and release of viral particles [11]. One virus in particular that is of global concern is the Cytomegalovirus (CMV), which belongs to the Herpesviridae family of adenoviruses [12]. In most cases CMV does not show any symptoms in an individual because the virus lies dormant throughout the person’s life, unless activated by a weakened immune system. CMV is usually spread through body fluids and sexual contact or through blood ...view middle of the document...

Letermovir has a molecular weight is 572.55 g/mol. The pharmacokinetic properties of Letermovir have been monitored but are still currently in trial phase. It has been reported that after a single oral dose, an average Tmax is reached after 1.5 hours, and it has a half-life of 10 hours [13]. Letermovir was developed by AiCuris and was bought by Merck through a subsidiary to further fund the trial stages.
Antibacterial: Bacteria cause disease in humans when they are able to reproduce in the body and produce harmful toxins which can damage tissue and organs. In nature these bacteria also produce agents called antibiotics which are used to protect against other bacterial competitors. All antibiotics work by disrupting a critical function in the bacterial cell [14]. A very well-known example is Penicillin. It was discovered in 1928 by Alexander Fleming and it works by preventing the cell from renewing its cell wall during growth. Eventually the cell wall weakens and burst, killing the bacterium. Unfortunately, bacteria can become resistant to antibiotics by changing their biochemistry in ways that prevent damage caused by antibiotics. Moreover, bacteria reproduce at such a high rate that the difficulty of controlling infections caused by bacteria is a major task facing researchers. Therefore, new antibiotic drugs or derivatives of previous antibiotic drugs are steadily being produced. One such drug that is used to treat moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients is Neutrexin [14].

Neutrexin, also known as Trimetrexate, contains a quinazoline to which a trimethoxyphnyl is attached to the seventh carbon. It has a molecular weight of 563.56 g/mol. The pKa of trimetrexate free base in 50% methanol/water is 8.0 [15]. The typical dose of intravenous Neutrexin along with leucovorin has an average clearance of 38mL/min/m2 and volume of distribution at steady state was 20 L/m2 with a half-life of 11 hours [15]. The drug is not given orally. Nuetrexin was produced by Ben Venue Laboratories, a subsidiary of Boehringer Ingelheim.
The mechanism of trimetrexate works as a competitive inhibitor of dihydrofolate reductase (DHFR) in bacteria and other microbes [14]. DHFR in bacteria catalyzes intracellular dihydrofolate to the active coenzyme tetrahydrofolate [14]. Inhibition of DHFR results in the depletion of this coenzyme, which also leads to the inhibition of thymidylate and subsequently purine biosynthesis [14]. Thus, bacteria will suffer from a disruption of DNA, RNA, and protein synthesis, which will lead to cell death. The reason why Leucovorin must be co-administered along with Neutrxen is that it increases the bioactivity of Neutrexin in bacteria selectively. Leucovorin provided a source of folates which compete with the trimetrexate. Bacteria do not have the ability to transport Leucovorin into the cell. Thus, at therapeutic doses Neutrexin can selectively target the Pneumocystis carinii organism which...

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