Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • A pyrimidine class of compounds

    2022-06-28

    A pyrimidine class of compounds is of enormous interest within anti-HIV drug PRT062070 discovery process for several decades, as pyrimidine based DABOs class [7], DAPYs class [8] are well known as NNRTIs as well as NRTIs. However, the overall role of a pyrimidine class of heterocycles in anti-HIV drug discovery appeared in the literature few years ago [9]. In connection with the present article, the inhibitory effects of dihydro-alkoxyl-benzyl-oxopyrimidine derivatives towards reverse transcriptase enzyme of HIV virus particle is recently reviewed [10]. Simultaneously, occurrence of similar pyrimidine congeners with potent anti-HIV integrase inhibitory profiles have been noticed by us and reviewed herewith. Developing the effective part of the pyrimidine ring system against RT enzyme of HIV, some scientists tried to provide latest pyrimidine centered substances focusing on the integrase enzyme of HIV virus particle and such developments are described in this review. To the 3′-end of the HIV pol gene, a 32 kDa protein is encoded called HIV integrase enzyme [11]. Inhibition of HIV integrase, accountable for placing the viral DNA into the host cellular genome, outcomes in arrest of the HIV life PRT062070 and is, therefore, a very eye-catching therapeutic target. Upon inhibition of integrase, the viral DNA is turned into a circular DNA incapable to be incorporated into the host genome [12]. Incorporation of viral DNA into the infected individual's chromosomal DNA, which is catalyzed by HIV integrase, happens by a particularly described series of 3′-processing and strand transfer reactions [13], [14]. In the cytoplasm, prior to the commencement of integration, there is set up of viral DNA, formerly created by reverse transcription, on HIV integrase. From each 3′-end of the viral DNA, after the assembly formation, a site-specific endonucleatic cleavage of two nucleotides is a process called 3′-processing, which produces tailored viral DNA recessed by two nucleotides and with terminal CAOH-3′. The strand transfer step is followed then, which includes joining of viral DNA's each 3′-ends with host DNA's 5′-ends via staggered nicking of chromosomal DNA. Remarkably, in the nucleus, the strand transfer step is partitioned from 3′-processing and is carried out after the transport of the processed, preintegration complex (formed through RT enzyme) from the cytoplasm into the nucleus [15].
    HIV integrase inhibitory activity of pyrimidones Pyrimidine entity is the essential ring found in the core structure of all essential nucleobases. The anti-HIV drug discovery within pyrimidine class of nucleoside scaffolds initiated with the synthesis of pyrimidine 3′-azido-2′,3′-dideoxynucleosides and 3′-substituted purine and pyrimidine 2′,3′-dideoxynucleosides and the discovery of AZT [16] inspired several researchers in the world to develop newer NRTIs class of anti-HIV drugs and such attempts then resulted in the discovery of several potent anti-HIV drugs like abacavir, emtricitabine, lamivudine, didanosine, apricitabine, stampidine, elvucitabine, racivir, amdoxovir, stavudine, zalcitabine, festinavir and tenofovir (Fig. 1). In addition to the pyrimidine class of NNRTIs, an FDA approved drug (12th October 2007) Raltegravir [17], [18] is the best example of a pyrimidone class of HIV-1 INIs targeting strand transfer function. Raltegravir (N-[(4-fluorophenyl)methyl]-1,6-dihyro-5-hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl] amino]ethyl]-6-oxo-4-pyrimidinecarboxamide monopotassium salt) can be synthesized according to the chemical transformation shown in Scheme 1[19]. Raltegravir has in vitro IC95 level of 31 ± 20 nmol/L against HIV-1 type in human CD4 cells with 83% binding to human plasma proteins with a huge range of potency against drug-resistant and wild-type HIV mutant strains. In some cases, the drug was found active against HIV-2 too, with 6 mmol/L of IC95 level as inspected in CEMx174 cells [20]. During the life cycle of HIV within CD4 cell, reverse transcriptase, a key enzyme of HIV virus particle forms the preintegration complex, which allows passing of HIV-1 viral DNA into the nucleus, where DNA strand transfer happens. Then, viral DNA is bonded to the integrase enzyme of HIV virus particle and links it with host CD4 cell DNA. After this process viral DNA is then sealed in the chromosome via viral cellular repair activities. Catalytic core, is the main part of the integrase enzyme and its divalent cations enables this enzyme to create covalent bonds with a phosphodiester backbone of DNA. The drug Raltegravir suppress this formation of covalent bond with CD4 cell DNA hence inhibits the activity of integrase enzyme [21], [22] (Fig. 2). It has highly efficient pharmacokinetic profile [23], [24] and well tolerance among a variety of HIV infected individuals as confirmed during clinical trials [25], [26], [27], [28], [29], [30] (see Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig. 7, Fig. 8, Fig. 9, Fig. 10, Fig. 11, Fig. 12, Fig. 13, Fig. 14, Fig. 15, Fig. 16, Fig. 17, Fig. 18, Fig. 19).