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    • Following the discovery of diketo

    2021-10-12

    Following the discovery of β-diketo compounds S-1360 [31] and L-731988 [32] as anti-HIV integrase inhibitors, a group of researchers discovered a potent dantrolene sodium mg based derivative (1) as the inhibitor of HIV integrase functioning at the 3′-processing and strand transfer steps of HIV integrase. Bioassay examining the inhibition of wild-type HIV-1 integrase by 1, indicated 3.7 μM and 0.2 μM of IC50s against 3′-processing and strand transfer, respectively. Compound 1 inhibited HIV-1TEKI and HIV-1NL4-3 strains with 50 nM and <20 nM of IC50s and >200 of CC50 level with >4000 and >10,000 selectivity indexes, respectively in PBMC cells, which was even better than the selectivity of AZT with >7143 and >5556 of SI, respectively. In addition, three more congeners of 1 were generated as bis-(o-F-Bn) analogue of 1, bis-(p-F-Bn) analogue of (1) and 1 minus N3-benzyl, which indicated 4.1 μM, 3.9 μM and 10 μM as well as <0.6 μM, <0.7 μM and 0.5 μM of IC50s against 3′-processing and strand transfer, respectively [33]. Some dihydroxypyrimidine carboxamides (2) were synthesized and checked for their HIV integrase strand transfer suppression action. SAR at carboxamide (2a), heteroaryl amide (2b) and benzylamide (2c) was determined and analogues 2c exhibited good potency than the remaining two series, in which compounds 2c, 2c, 2cx, 2c and 2c exerted 40 nM, 50 nM, 20 nM, 10 nM and 10 nM of IC50s, respectively. The last two analogues were the most potent among the all tested to suppress IN enzyme. Furthermore, compounds 2a, 2a, 2a, 2a and 2b–2b furnished 20 nM, 30 nM, 40 nM, 20 nM, 10 nM, 50 nM and 20 nM of IC50s, respectively, suggesting the class of compounds as promising inhibitors of HIV integrase enzyme targeting at strand transfer in addition to the indentification of p-fluorobenzylamide as optimal entity for the potency [34]. Simultaneously, some 4,5-dihydroxypyrimidine carboxamides (3a and 3b) and N-alkyl-5-hydroxypyrimidinone carboxamides (3c) were developed and checked for their in vitro inhibitory potency in the cellular HIV spread assay against HIV integrase strand transfer function [35]. Analogues 3a, 3b–3b and 3c–3c appeared with 0.01–0.20 μM of IC50s (the concentration of inhibitor that reduces HIV integrase activity by 50%) as well as 0.065–>10 μM of CIC95s. Analogues 3b and 3c were the most potent HIV integrase inhibitors in this study with very good pharmacokinetics in preclinical species like rat, dog and rhesus. A series of N-benzyl-5,6-dihydroxypyrimidine-4-carboxamides (4) were further equipped to screen against HIV integrase strand transfer suppression and in designing these molecules, p-fluorobenzylamide was introduced constantly, whereas different substituents were introduced at 2nd position as unsubstituted or alkyl or phenyl or benzyl or fluorophenyl or heteroaryl congeners (4i–4xv), cyclic amine congeners (4xvi–4xxvi) as well as acyclic amine derivatives (4xxvii–4xxxix). All compounds expressed 0.008–2 μM of strand transfer IC50s. However, final derivatives with acyclic amines were the most potent ones followed by cyclic amines and then remaining. Compounds indicated 0.04–>10 μM of CIC95 values using HIV-1IIIB and MT-4 cells, in a medium containing 10% heat-inactivated fetal bovine serum. The most potent compounds in enzymatic and cellular assays was 4xxxiii with promising pharmacokinetic profiles in rat, dog, and rhesus monkeys, and suggest the class of compounds as potential leads for further anti-HIV integrase drug discovery [36]. The research within dihydroxypyrimidines and N-methylpyrimidones class of compounds furthered upon the construction of few more derivatives of these classes as 2-pyrrolidinyl-N-methylpyrimidones (5a–5a), N-methylpyrimidones bearing six membered heterocycles at 2nd position (5a–5a) as well as 2-piperazinyl (5a–5a) and 2-morpholinyl-N-methylpyrimidones (5b–5b) [37] indicating 10–62 nM, 21–70 nM, 4–52 nM as well as 15–60 nM of IC50s, respectively inhibiting HIV integrase strand transfer. During HIV replication assay, the CIC95 levels within 10% FBS for all these compounds ranged from <0.03 to 2.50 μM, 0.05 to >1.0 μM, 0.03 to 0.50 μM as well as 30 to >1000 μM, respectively. The most potent derivative was analogue 5c with potent enzymatic activity and favorable pharmacokinetic measurements.