Synthesis and biological evaluation of novel 5-alkyl-2-arylthio-6-((3,4-dihydroquinolin-1(2H)-yl)methyl)pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors

Synthesis, Polymorphism, and Insecticidal Activity of Methyl 4‐(4‐chlorophenyl)‐8‐iodo‐2‐methyl‐6‐oxo‐1,6‐dihydro‐4H‐pyrimido[2,1‐b]quinazoline‐3‐Carboxylate Against Anopheles arabiensis Mosquito

“…For example, the substituted dihydropyrimidine ring system exhibited numerous pharmacological activities such as antibacterial , anticancer , antifungal , antihypertensive , antiinflammatory , and antitubercular properties . Some of the substituted dihydropyrimidine derivatives have been used as dipeptidyl peptidase‐IV (DPP‐4) inhibitors and non‐nucleoside HIV‐1 reverse transcriptase inhibitors . Among the dihydropyrimidine pharmacophores, wide spectrum of biological activities include larvicide actions against mosquitoes .…”

Synthesis and Biological Evaluation of a Series of 2‐((1‐substituted‐1H‐1,2,3‐triazol‐4‐yl)methylthio)‐6‐(naphthalen‐1‐ylmethyl)pyrimidin‐4(3H)‐one As Potential HIV‐1 Inhibitors

“…The results revealed that six target compounds ( B5b1 , B5B3 – B5b7 ) had remarkable activities against WT HIV‐1, with EC 50 values in the low micromolecular range, which was better than that of DDI (EC 50 = 23.20 μ m ). Even so, they were less active in comparison with the previously reported C‐2 substituted S‐DABO derivatives and other reference drugs . The most active compound 4‐((4‐((4‐(2,6‐dichlorobenzyl)‐5‐methyl‐6‐oxo‐1,6‐dihydropyrimidin‐2‐ylthio)methyl)‐1H‐1,2,3‐triazol‐1‐yl)methyl)benzenesulfonamide ( B5b7) showed activity with EC 50 value of 3.22 μ m comparable to that of 3TC (EC 50 = 2.24 μ m ).…”

“…The synthetic route of the newly designed compounds is described in Scheme . The key intermediate β ‐ketoesters ( A2a , A2b , B2a , B2b ) were prepared with a simple method previously used by us through the reaction of 2‐(naphthalen‐1‐yl)acetic acid ( A1 ) or 2‐(2,6‐dichlorophenyl)acetic acid ( B1 ) with N,N ′‐carbonyldiimidazole (CDI) followed by treatment with potassium 3‐ethoxy‐3‐oxopropanoate (a) or potassium 3‐ethoxy‐2‐methyl‐3‐oxopropanoate ( b ) in the presence of anhydrous MgCl 2 and Et 3 N. Next, the cyclization reaction of β ‐ketoesters ( A2a , A2b , B2a , B2b ) with thiourea in the presence of EtONa (in refluxing EtOH) afforded the substituted uracils ( A3a , A3b , B3a , B3b ). Treatment of these uracils with 3‐bromoprop‐1‐yne in the presence of K 2 CO 3 in anhydrous DMF gave the key alkyne intermediates ( A4a , A4b , B4a , B4b ).…”

“…Among them, MY‐4b3 was identified as the most potent molecule (EC 50 = 0.18 μ m , CC 50 > 243.56 μ m , SI > 1326). Moreover, a novel C‐2 thioethanone S‐DABO derivative JZ‐6c1 (EC 50 = 0.24 μ m ) was reported to demonstrate the improved or comparable HIV‐1 potency compared with NVP (EC 50 = 0.21 μ m ) and DLV (EC 50 = 0.32 μ m ) . As the C‐2 side chain of S ‐DABOs points toward the solvent exposed region and accommodated substantial modifications of the inhibitor NNRTIs, we postulate that the introduction of the thioacetanilide (in MY‐4b3) and thioethanone group (in JZ‐6c1) to the C‐2 side chain might be more favorable to improve specific protein–inhibitor interactions, and further exploration of the plasticity of this part of the pocket may lead to the discovery of new S‐DABOs with improved pharmacokinetic properties without a significant loss of binding affinity.…”

Design, synthesis, and biological evaluation of novel 5‐Alkyl‐6‐Adamantylmethylpyrimidin‐4(3H)‐ones as HIV‐1 non‐nucleoside reverse‐transcriptase inhibitors

“…Our previous work on S ‐DABOs disclosed that a tetrahydroquinolylmethyl group at C‐6 position of the pyrimidinone ring resulted in compounds with moderate anti‐HIV‐1 activity. Among them, compound 1 had proved to be the most potent compound (EC 50 = 0.24 μ m ), which was compared to nevirapine (NVP) (EC 50 = 0.21 μ m ) and delavirdine mesylate (DLV) (EC 50 = 0.32 μ m ) (Figure S2) . Molecular modeling studies demonstrated that the C‐6 substituent of pyrimidinone core accommodating in the hydrophobic pocket of the HIV‐1 RT formed a large number of hydrophobic interactions with the side residues of Y181, Y188, and W229, which played an important role in the interactions between the RT and the inhibitors.…”