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  • Compound a substituted phenyl H pyrano

    2022-01-14

    Compound 6, a 5-(4-substituted-phenyl)-5H-pyrano[2,3-d:-6,5-d′]dipyrimidine derivative was invented previously to have significant efficacy to inhibit HIV integrase enzyme with 0.9 ± 0.4 μM of IC50 against 3′-processing and 16.1 ± 10.7 μM of IC50 against strand transfer suppression. The compound indicated 0.3 ± 0.2 μM of IC50 against overall integration of HIV [38] and also indicated good inhibition of HIV enzyme reverse transcriptase, hence confirming that some pyrimidine entities can be used as dual HIV inhibitors. A group of researchers yielded a further class of compounds as substituted 2,4-dioxo-3,4-dihydropyrimidin-4-oxobutenoic WAY-100635 maleate salt mg derivatives (7c) with dual anti-HIV action against RT and IN enzymes which was rationalized from the well known RT inhibitor 7a and IN inhibitor 7b. Compounds 7c–7c indicated 1.8 μM, 4.4 μM, 2.4 μM and 7.7 μM of IC50s against IN enzyme and >10 μM of CC50s, respectively, whereas against HIV replication, these analogues furnished 0.052 μM, 0.0097 μM, 0.033 μM and 0.017 μM of IC50s with tremendous selectivity indexes of >190, >1000, >310 and >600, respectively [39]. In ongoing studies by the same research group, synthesis of pyrimidine and quinolone conjugates was carried out to yield dual anti-HIV inhibitors of RT and IN. In this context, a series of compounds (7d) were checked for their in vitro potency against HIV strand transfer [40]. Compounds 7d–7d exhibited 35 μM, 41 μM, 51 μM and 19 μM of IC50s against the HIV integrase enzyme, respectively, whereas suppressed HIV replication with 0.22 μM, 0.21 μM, 1.5 μM and 2.2 μM of EC50s (compound dose required to achieve 50% protection of MT-4 cells from HIV-l-induced cytopathicity), respectively. Compounds inhibited RT enzyme with IC50s ranging from 1.1 to 3.7 μM. Overall SAR suggested that varying the conjugated ring systems may lead to further variations in anti-HIV action as well as the mode of action of the resultant analogues; hence the class of compounds warrants further studies in anti-HIV IN drug discovery. 3-Hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylates (8) were synthesized and checked to achieve highly efficient strand transfer inhibition. The structural variation was carried out as simple amine substituents (8a), amide substituents (8b) as well as oxalamide substitution (8c) at position 9 of the bicyclic scaffold, in which the strand transfer bioassay results revealed that compounds 8a, 8a, 8a, 8a and 8a expressed 20 nM, 36 nM, 18 nM, 9 nM and 24 nM of inhibitory concentration (IC50), respectively. Analogues 8b, 8b, 8b and 8b furnished 23 nM, 21 nM, 21 nM and 18 nM of IC50s, respectively, whereas, all oxalamide scaffolds (8c–8c) exhibited 18–36 nM of IC50s and was the most potent class of compounds studied in this research. Furthermore, all compounds did not indicate any cytotoxic nature up to a concentration level (CC50) of 50 μM, hence suggesting the types of analogues as a potent anti-HIV IN inhibitors. During the cellular spread assay under 10% FBS serum condition, compounds 8c–8c showed 31–62 nM of CIC95 level expressing their potential efficacies to inhibit HIV replication as new leads [41]. In continuous studies, few more bicyclic, N-(4-Fluorobenzyl)-3-hydroxy-9,9-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrazino [1,2-a]pyrimidine-2-carboxamides (9) were equipped and checked for their potency against HIV integrase strand transfer. This was the class of bicyclic-pyrimidine class of heterocycles like bicyclic pyrimidones (9a) and their N-substituted congeners with the reduced basicity (9b and 9c) as well as their N-aryl/heteroaryl-substituted analogues (9d). The anti-HIV strand transfer bioassay results indicated that compounds 9a–9a appeared with 5 nM, 7 nM, 16 nM, 6 nM and 20 nM of IC50s, compounds 9b–9b exhibited 3 nM, 5 nM, 21 nM, 8 nM, 7 nM, 7 nM, 21 nM, 8 nM and 5 nM of IC50s, derivatives 9c–9c expressed 5 nM, 6 nM, 10 nM, 15 nM and 8 of IC50s, as well as all compounds 9d (except 9d) furnished 2–25 nM of IC50s, respectively. SAR on such a huge variety of structural analogues suggested that five membered heterocycle provided better potency than six membered ones and tethering the N-methyl group of the pyrimidones onto the amino gem-dimethyl group was essential to equip a potent series of bicyclic HIV integrase inhibitors having equipotent action as Raltegravir [42]. During the HIV replication assay, compounds 9a–9c indicated moderate inhibition; however, several analogues from 9d series exhibited 7–62 nM of CIC95s in 10% FBS.