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    • Development of few more dihydroxy pyrimidine and N

    2021-09-17

    Development of few more dihydroxy-pyrimidine and N-methylpyrimidone analogues as HIV-integrase inhibitors was attempted involving substitution of variety of five- and six-membered rings via the introduction of a simple methyl substituent in the α-position of the C-2 side chains in order to improve passive membrane permeability. Compounds (R1 = H) 10a, 10a, 10a, 10a, 10a, 10a, 10a, 10b, 10b, 10b, 10b and 10b showed 20 nM, 20 nM, 14 nM, 20 nM, 4 nM, 20 nM, 15 nM, 20 nM, 30 nM, 6 nM, 20 nM and 30 nM of IC50s, respectively towards HIV IN strand transfer inhibition, whereas, compounds 10a, 10a, 10a, 10a, 10a, 10a, 10b and 10b demonstrated 90 nM, 80 nM, 60 nM, 40 nM, 20 nM, 4 nM, 60 nM and 40 nM of CIC95 values, respectively, in the HIV replication assay in the presence of 10% FBS. The most potent, highly active palovarotene was 10a with 4 nM of anti-HIV replication potency and highly comparable to that of Raltegravir (19 nM). All active derivatives showed good passive membrane permeability when checked in parallel artificial membrane permeability assays. SAR indicated that the α-methyl derivatives have better pharmacokinetic profiles than the corresponding des-methyl analogs when tested in vivo in rats [43]. Several new pyrimidinones (11) with derivatization at N-1, C-2 and N-3 sites were constructed and evaluated for their in vitro anti-HIV IN inhibitory potencies. Compounds 11a–11f demonstrated 11 μM, 22 μM, 16 μM, 14 μM, 7.4 μM, 8.2 μM of anti-HIV IN IC50s, whereas analogues 11i–11k indicated 8 μM, 12 μM and 37 μM of anti-HIV IN IC50s, respectively. The remaining derivatives were found to reveal moderate inhibition of HIV IN around 100 μM of IC50s. The active analogues were not having cytotoxic nature and compounds 11a–11d were having >220, 560, 56 and >710 of selectivity indexes, and 0.46 μM, 0.17 μM, 0.56 μM and 0.014 μM of EC50s anti-HIV replication assay, respectively. The compounds also exhibited excellent inhibition of HIV RT enzyme with EC50s ranging from 0.028 to 0.71 μM and can be regarded as the potent dual inhibitors of HIV IN and RT. The types of compounds can be considered for developing a further class of potent HIV IN inhibitors in ongoing studies [44]. 2-Pyrrolidinyl-N-methylpyrimidones (12) were generated and variation (SAR) among structural features were carried out in terms of pyrrolidine N-substitution SAR (12a) and benzylamide SAR on pyrrolidine amides and carbamates (12b and 12c). All final derivatives were screened for their in vitro inhibitory efficacy towards HIV IN enzyme. Compounds 12a-12a showed 23 nM, 20 nM, 10 nM, 15 nM, 10 nM, 10 nM, 15 nM, 9 nM, 10 nM and 21 nM of IC50s, whereas, analogues 12b, 12b, 12b, 12c and 12c exerted 24 nM, 27 nM, 32 nM, 20 nM and 19 nM of IC50s indicating excellent enzymatic activity and efficacy at inhibiting viral spread in the cell-based assay, respectively. In general, agreeing to the continuous trend, it was found that alteration of benzylamide entity in the core structure lead to the diminished potencies of the resultant analogues, while derivatizing pyrimidine ring showed a wide range of different potencies of furnished scaffolds. However, it is to be noted that, alteration of 4-fluorobenzylamide fragment lead to the development of compounds having improved pharmacokinetic profiles in rat than those similar entities studied before. Against HIV replication, compounds 12a (except 12a and 12a) showed 14–63 nM of EC50s in the presence of 10% FBS, while analogues 12c and 12d furnished 3–16 nM of EC50s in similar bioassay, identifying the class of compounds a potential leads to develop further anti-HIV IN inhibitory candidates. Overall, compound 12b was the most potent analogues among all studied in this research including significant pharmacokinetic profiles in rat and dog. Hence, the compound was further studied for its wide potential against several HIV IN mutant strains as T66I, V151I, F121Y, T125K, M154I, S153Y, N155S and L74M, in which it indicated 1, 1, 1.5, 1, 0.8, 0.8, 8, and 2.5, respective shift in IC50s relative to wild type HIV-1 [45]. Furthermore, a group of researchers attempted benzyl repositioning within the pre-established pyrimidones and the structural variation resulted into the development of some new candidates (13i–13vii) having 111 μM, 169 μM, 206 μM, >333 μM, 243 μM and 241 μM of IC50s, respectively against HIV integrase strand transfer, whereas against HIV IN 3′-processing, the IC50s were >333 μM for all analogues, hence conforming the unique mode of action of such derivatives as HIV IN strand transfer. However, from the bioassay results of this particular study, it can be noted that benzyl group repositioning denied the expected potencies, hence suggesting its key role and key position within the mentioned types of core scaffolds [46], however such scaffold rearrangements may offer possibilities to construct new compounds inhibiting HIV IN 3′-processing.