Systematic evaluation of methyl ester bioisosteres in the context of developing alkenyldiarylmethanes (ADAMs) as non-nucleoside reverse transcriptase inhibitors (NNRTIs) for anti-HIV-1 chemotherapy

Challenges and approaches in the discovery of human immunodeficiency virus type‐1 non‐nucleoside reverse transcriptase inhibitors

“…The inhibitory activity on the K103N variant obtained with compound 19, which bears the S-methyl thioester moiety, was only twofold lower than that obtained on WT HIV-1. Based on these results and those obtained by X-ray analyses, it can be concluded that binding of the imidoyl halide is more dependent on the interaction with K103 than with the thioester group 15 (Figure 18). DOV (30) is a novel NNRTI that is administered once daily, which has activity against many NNRTI-resistant HIV variants and low potential for drug interactions.…”

“…Great progress has been made in the optimization of different classes of NNRTIs through the application of traditional medicinal chemistry strategies, such as bioisosteric replacement, molecular hybridization, or scaffold hopping. Excellent examples are the development of NVP analogs, DAPY derivatives, and ADAMS . Computational chemistry has also allowed significant progress in NNRTI optimization.…”

“…Excellent examples are the development of NVP analogs, DAPY derivatives, and ADAMS. 15,22,88 Computational chemistry has also allowed significant progress in NNRTI optimization. In combination with crystallographic analysis, the development of comprehensive butterfly-like and horseshoe-like pharmacophores allowed the identification of the required structural features for NNRTI activity and the understanding of RT-drug interactions.…”

Recent Advances in the Design and Development of Non‐nucleoside Reverse Transcriptase Inhibitor Scaffolds

“…[44] Extensive chemical modificationsw ere done by Cushmanand co-workers, who incorporated N-methoxyimidoyl halidesa sb ioisosteres of methyl esters into the ADAM structure. [45] ADAMs 69 a, 70,a nd 71 demonstrated high activity againstb oth HIV-1 (RF) in CEM-SS cells and HIV-1 (IIIB) in MT-4 cells at EC 50 values in the sub-micromolar range ( Figure 34). Moreover,c ompounds 69 a and 69 b were active againstt he common mutantH IV-1 strain K103N at EC 50 valueso f0 .55 and 0.78 mm,r espectively.…”

“…Some research groups designed and optimized these types of NNRTIs by replacing the methyl carboxylate with its stable bioisosteres . Extensive chemical modifications were done by Cushman and co‐workers, who incorporated N ‐methoxyimidoyl halides as bioisosteres of methyl esters into the ADAM structure . ADAMs 69 a , 70 , and 71 demonstrated high activity against both HIV‐1 (RF) in CEM‐SS cells and HIV‐1 (IIIB) in MT‐4 cells at EC 50 values in the sub‐micromolar range (Figure ).…”