RESUMEN
In the current antiretroviral landscape, continuous efforts are still needed to search for novel chemotypes of human immunodeficiency virus type 1 (HIV-1) inhibitors with improved drug resistance profiles and favorable drug-like properties. Herein, we report the design, synthesis, biological characterization, and druggability evaluation of a class of non-nucleoside reverse transcriptase inhibitors. Guided by the available crystallographic information, a series of novel indolylarylsulfone derivatives were rationally discovered via the substituent decorating strategy to fully explore the chemical space of the entrance channel. Among them, compound 11h bearing the cyano-substituted benzyl moiety proved to be the most effective inhibitor against HIV-1 wild-type and mutant strains (EC50 = 0.0039-0.338 µM), being far more potent than or comparable to etravirine and doravirine. Besides, 11h did not exhibit cytotoxicity at the maximum test concentration. Meanwhile, the binding target of 11h was further confirmed to be reverse transcriptase (IC50 = 0.055 µM). Preliminary structure-activity relationship were discussed to guide further optimization work. Molecular docking and dynamics simulation studies were investigated in detail to rationalize the biological evaluation results. Further drug-likeness assessment indicated that 11h possessed excellent physicochemical properties. Moreover, no apparent hERG blockade liability and cytochrome P450 inhibition were observed for 11h. Notably, 11h was characterized by favorable in vitro metabolic stability with moderate clearance rates and long half-lives in human plasma and liver microsomes. Overall, 11h holds great promise as an ideal Anti-HIV-1 lead compound due to its potent antiviral efficacy, low toxicity, and favorable drug-like profiles.
Asunto(s)
Fármacos Anti-VIH , Diseño de Fármacos , VIH-1 , Simulación del Acoplamiento Molecular , Inhibidores de la Transcriptasa Inversa , Sulfonas , VIH-1/efectos de los fármacos , Humanos , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Relación Estructura-Actividad , Sulfonas/farmacología , Sulfonas/síntesis química , Sulfonas/química , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/metabolismoRESUMEN
Edgeworthianins A-E (1-5) were isolated from Edgeworthia chrysantha as a class of macrocyclic daphnane orthoesters with an unusual macrocyclic ring formed from a C14 aliphatic chain. Their structures were elucidated by extensive physicochemical and spectroscopic analyses. Compounds 2, 4, and 5 exhibited potent anti-HIV activity against HIV-1 infection of MT4 cells with EC50 values of 29.3, 8.4, and 2.9 nM, respectively. These compounds broaden the findings of the structure-activity relationship of macrocyclic daphnane orthoesters for further anti-HIV drug development.
Asunto(s)
Fármacos Anti-VIH , Diterpenos , Thymelaeaceae , Diterpenos/química , Thymelaeaceae/química , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/química , Relación Estructura-Actividad , Estructura MolecularRESUMEN
From the whole plant of Daphne pedunculata, 12 macrocyclic daphnane diterpenoids, including six new compounds, daphnepedunins A-F (1-4, 9, and 10), were isolated. Their structures were elucidated by physiochemical and spectroscopic data analysis, the modified Mosher's method, and X-ray crystallography. The isolated compounds were evaluated for anti-HIV activity against HIV-1 infection in MT4 cells and showed significant anti-HIV activity with IC50 values of 36.3-994 nM. A consideration of the anti-HIV activity of these compounds provided further insight into the structure-activity relationships of macrocyclic daphnane diterpenoids.
Asunto(s)
Fármacos Anti-VIH , Daphne , Diterpenos , Thoracica , Animales , Daphne/química , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/química , Diterpenos/farmacología , Diterpenos/química , Estructura MolecularRESUMEN
Four new diterpene esters, shirakindicans A-D (1-4), along with eight related known diterpene esters (5-12), were isolated from the fruits of the Bangladeshi medicinal plant Shirakiopsis indica. The structures of 1-4 were elucidated by spectroscopic data analysis and electronic circular dichroism (ECD) calculations. Shirakindican A (1) was assigned as a tigliane-type diterpene ester possessing an unusual 6ß-hydroxy-1,7-dien-3-one structure, while shirakindican B (2) exhibits a tiglia-1,5-dien-3,7-dione structure. The anti-HIV activities of the isolated diterpene esters were evaluated and showed significant activities for sapintoxins A (5) and D (11), with EC50 values of 0.0074 and 0.044 µM, respectively, and TI values of 1â¯100 and 5â¯290. Sapatoxin A (12) also exhibited anti-HIV activity with an EC50 value of 0.13 µM and a TI value of 161.
Asunto(s)
Fármacos Anti-VIH , Euphorbiaceae , VIH , Ésteres del Forbol , Euphorbiaceae/química , Frutas/química , Estructura Molecular , VIH/efectos de los fármacos , Ésteres del Forbol/química , Ésteres del Forbol/aislamiento & purificación , Ésteres del Forbol/farmacología , Fármacos Anti-VIH/química , Fármacos Anti-VIH/aislamiento & purificación , Fármacos Anti-VIH/farmacología , Línea Celular , HumanosRESUMEN
Tigliane-type diterpenoids have attracted much attention in drug discovery since they have been reported to exhibit remarkable biological effects, such as tumor-promoting, antineoplastic, and anti-HIV activities. In continuing our efforts to discover novel biologically important diterpenoids from Wikstroemia species, Wikstroemia lichiangensis was investigated phytochemically for the first time. As a result, four new (1-4) and one known (5) tigliane-type diterpenoid were isolated, and their structures were elucidated by spectroscopic data analysis. Tiglianes (1-5) showed potent anti-HIV activity against HIV-1 infection of MT4 lymphocytes with IC50 values of 1.1-65.4 nM.
Asunto(s)
Diterpenos , Forboles , Wikstroemia , Diterpenos/química , Diterpenos/farmacología , Estructura Molecular , Componentes Aéreos de las Plantas , Wikstroemia/químicaRESUMEN
Twenty-one new iridoids, jatamansidoids A-U (1-12, 21-26, 32, 35 and 36), two new natural ones, jatamansidoids V (37) and W (38), eighteen known ones (13-20, 27-31, 33 and 34), together with three patchoulol-type sesquiterpenoids (39-41), were isolated from the roots and rhizomes of Valeriana jatamansi. Structurally, compounds 1-7 were the first examples of iridoids from V. jatamansi with unique α, ß, γ, δ-unsaturated aldehyde fragment between C-11, C-4, C-5, C-9 and C-8; compound 8 was an unprecedented iridoid derivative with a methyl group (Me-10) at C-1, rather than C-8, and its plausible biogenetic pathway was proposed in this paper; compounds 22 and 23 were the first examples of Δ4(5)-iridoids simultaneously replaced by oxygen-containing groups at C-3, C-6 and C-7; compound 24 was the first iridoid with both 6,7- and 1,10-epoxy fragments. The structures and absolute configurations of new compounds were elucidated based on extensive spectroscopic techniques and quantum chemical calculation. Furthermore, compounds 13-15 and 39-41 exhibited potent anti-influenza virus activities with H1N1 and H3N2 strains, with IC50 values of 0.21-1.48 µM.
Asunto(s)
Subtipo H1N1 del Virus de la Influenza A , Nardostachys , Sesquiterpenos , Valeriana , Subtipo H3N2 del Virus de la Influenza A , Iridoides/química , Iridoides/farmacología , Estructura Molecular , Raíces de Plantas/química , Sesquiterpenos/química , Sesquiterpenos/farmacología , Valeriana/químicaRESUMEN
COVID-19, caused by the highly transmissible severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has rapidly spread and become a pandemic since its outbreak in 2019. We have previously discovered that aloperine is a new privileged scaffold that can be modified to become a specific antiviral compound with markedly improved potency against different viruses, such as the influenza virus. In this study, we have identified a collection of aloperine derivatives that can inhibit the entry of SARS-CoV-2 into host cells. Compound 5 is the most potent tested aloperine derivative that inhibited the entry of SARS-CoV-2 (D614G variant) spike protein-pseudotyped virus with an IC50 of 0.5 µM. The compound was also active against several other SARS-CoV-2 variants including Delta and Omicron. Results of a confocal microscopy study suggest that compound 5 inhibited the viral entry before fusion to the cell or endosomal membrane. The results are consistent with the notion that aloperine is a privileged scaffold that can be used to develop potent anti-SARS-CoV-2 entry inhibitors.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Inhibidores de Fusión de VIH , Quinolizidinas , Humanos , Pandemias , Quinolizidinas/farmacología , SARS-CoV-2 , Internalización del VirusRESUMEN
Tigliane esters show many biological activities, including anti-HIV-1 activity. Our aim in this study was to establish structure-anti-HIV activity relationships for four series of tigliane-type diterpenoids. We synthesized and evaluated 29 new phorbol ester derivatives for anti-HIV activity and for cytotoxicity against human tumor cell lines. Among them, three derivatives, two phorbol-13-monoesters (5d and 5e) and a phorbol-12,13-diester (6a), showed significant anti-HIV activity. We found that better anti-HIV activity was often associated with a shorter acyl ester at C-13. Particularly, compounds with a phenyl ring in the ester side chain exhibited excellent anti-HIV activity and had good safety indexes. Due to its significant anti-HIV potency with a high selectivity index, phorbol-12,13-dicinnamoate (6a) was chosen as the potential candidate for further preclinical trials.
Asunto(s)
Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , VIH-1/fisiología , Ésteres del Forbol/química , Ésteres del Forbol/farmacología , Replicación Viral/efectos de los fármacos , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The HIV-1 Capsid (CA) is considered as a promising target for the development of potent antiviral drugs, due to its multiple roles during the viral life cycle. Herein, we report the design, synthesis, and antiviral activity evaluation of series of novel phenylalanine derivatives as HIV-1 CA protein inhibitors. Among them, 4-methoxy-N-methylaniline substituted phenylalanine (II-13c) and indolin-5-amine substituted phenylalanine (V-25i) displayed exceptional anti-HIV-1 activity with the EC50 value of 5.14 and 2.57 µM respectively, which is slightly weaker than that of lead compound PF-74 (EC50 = 0.42 µM). Besides, surface plasmon resonance (SPR) binding assay demonstrated II-13c and V-25i prefer to combine with CA hexamer rather than monomer, which is similar to PF-74. Subsequently, molecular dynamics simulation (MD) revealed potential interactions between representative compounds with HIV-1 CA hexamer. Overall, this work laid a solid foundation for further structural optimization to discover novel promising HIV-1 CA inhibitors.
Asunto(s)
Fármacos Anti-VIH/farmacología , Proteínas de la Cápside/antagonistas & inhibidores , Diseño de Fármacos , VIH-1/efectos de los fármacos , Fenilalanina/farmacología , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Proteínas de la Cápside/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , VIH-1/metabolismo , Humanos , Pruebas de Sensibilidad Microbiana , Simulación de Dinámica Molecular , Estructura Molecular , Fenilalanina/síntesis química , Fenilalanina/química , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Structurally diverse tigliane diterpenoids have drawn significant research interest for drug discovery over many decades. Using LC-MS-guided fractionation and separation, the first phytochemical investigation on Wikstroemia lamatsoensis led to the isolation of eight tiglianes (1-8), including two new compounds, wikstrocin D (1) and wikstrocin E (2). The new structures were elucidated based on extensive physicochemical and spectroscopic analyses. The characteristic ESIMS/MS fragmentations of tiglianes 1-8 were also summarized. Among the isolated tiglianes, three compounds (8, 5, and 7) showed the most potent anti-HIV activity, with IC50 values of 0.18, 3.8, and 12.8 nM, respectively.
Asunto(s)
Fármacos Anti-VIH/química , Diterpenos/química , Forboles/química , Wikstroemia/química , Fármacos Anti-VIH/farmacología , Línea Celular , China , Diterpenos/farmacología , VIH-1/efectos de los fármacos , Humanos , Estructura Molecular , Forboles/farmacología , Fitoquímicos/química , Fitoquímicos/farmacologíaRESUMEN
In the present work, we described the design, synthesis and biological evaluation of a novel series of potential dual-target prodrugs targeting the HIV-1 reverse transcriptase (RT) and nucleocapsid protein 7 (NCp7) simultaneously. Among them, the most effective compound 7c was found to inhibit HIV-1 wild-type (WT) strain at double-digit nanomolar concentration (EC50 = 42 nM) in MT-4 cells, and sub-micromole (EC50 = 0.308 µM) to inhibit HIV-1 NL4-3 strain in TZM-bl cells. This is a significant improvement over the parent drug MT. In addition, it showed moderate inhibitory potency (EC50 = 1.329 µM) against the HIV-1 K103N/Y181C double mutant strain (MT-4 cells). The metabolic stability in human plasma of compound 7c indicated that it can release the active forms of the parent drugs MT and AZT in a linear time-independent manner and turn out to be a potential prodrug.
Asunto(s)
Fármacos Anti-VIH/farmacología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , Profármacos/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/antagonistas & inhibidores , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Transcriptasa Inversa del VIH/metabolismo , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Profármacos/síntesis química , Profármacos/química , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/química , Relación Estructura-Actividad , Células Tumorales Cultivadas , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/metabolismoRESUMEN
Daphnane diterpenes with a 5/7/6-tricyclic ring system exhibit potent anti-HIV activity but are found in low abundance as plant natural products. In this study, an effective approach based on mass spectrometric fragmentation pathways was conducted to specifically recognize and isolate anti-HIV compounds of this type from Daphne genkwa. Briefly, the fragmentation pathways of reference analogues were elucidated based on characteristic ion fragments of m/z 323 â 295 â 267 or m/z 253 â 238 â 197 by ultra-high-performance liquid chromatography-ion trap tandem mass spectrometry (UPLC-IT-MSn) and then applied to the differentiations of substances with or without an oxygenated group at C-12. Twenty-seven daphnane diterpenes were successfully recognized from a petroleum ether extract of D. genkwa, including some potential new compounds and isomers that could not be identified accurately only from the ion fragments. Further separation of these target compounds using high-speed countercurrent chromatography (HSCCC) and preparative HPLC led to the isolation of three new (11, 25, and 27) and 14 known compounds, whose structures were identified and confirmed based on MS, NMR, and electronic circular dichroism (ECD) spectroscopy. The isolates exhibited anti-HIV activities at nanomolar concentrations. The results demonstrated that this strategy is feasible and reliable to rapidly recognize and isolate daphnane diterpenes from D. genkwa.
Asunto(s)
Daphne/química , Diterpenos/química , Diterpenos/farmacología , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida , Diterpenos/aislamiento & purificación , Espectroscopía de Resonancia Magnética , Estructura Molecular , Espectrometría de Masas en TándemRESUMEN
Five new [daphneodorins D-H (1, 5, and 10-12)] and seven known daphnane diterpenoids (2-4 and 6-9) were isolated from Daphne odora. The structures of the new compounds were elucidated by extensive physicochemical and spectroscopic analysis. The isolated compounds were evaluated for their anti-HIV activity against HIV-1 infection of MT4 cells. Nine daphnane diterpenoid orthoesters (1-9) showed potent anti-HIV activity with EC50 values of 1.5-7.7 nM.
Asunto(s)
Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Daphne/química , Diterpenos/química , Diterpenos/farmacología , Fármacos Anti-VIH/aislamiento & purificación , Línea Celular , Diterpenos/aislamiento & purificación , VIH/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Análisis Espectral/métodos , Relación Estructura-ActividadRESUMEN
Five new quinoline alkaloids, paliasanines A-E (1-5), and 17 known compounds (6-22) were isolated from a methanol extract of Melochia umbellata var. deglabrata leaves. Their chemical structures were elucidated by analysis of HRMS and 1D and 2D NMR spectroscopic data. Compounds 1-5 are the first naturally occurring 3,4-methylenedioxyquinolines incorporating an oxabicyclo[3.2.1]octane unit. Compounds 6 and 7 displayed selective cytotoxicity (IC50 5.9-8.4 µM) against A549 and MCF-7 cell lines, while compounds 1-5 were not active. Compounds 1-3 did not exhibit an anti-HIV effect in MT4 cells, although the related quinolone derivative waltherione A exhibited significant activity. These preliminary results indicate that the 3-methoxy-4-quinolone skeleton might be preferred for both antiproliferative and anti-HIV activities.
Asunto(s)
Alcaloides/química , Antineoplásicos Fitogénicos/química , Malvaceae , Extractos Vegetales/química , Quinolinas/químicaRESUMEN
During a chemical investigation of Wikstroemia scytophylla, three new [wikstrocins A-C (1-3)] and three known tigliane diterpenoids (4-6) were isolated. The structures of the new compounds were elucidated from extensive physiochemical and spectroscopic analysis. The correlations between the ECD Cotton effects and B ring structures of tiglianes were also evaluated. The isolated compounds were assessed for their anti-HIV activity against HIV-1 infection of MT4 cells, and two compounds (4 and 6) showed potent anti-HIV activity with IC50 values of 3.8 and 12.8 nM, respectively.
Asunto(s)
Fármacos Anti-VIH/farmacología , Diterpenos/farmacología , Forboles/farmacología , Wikstroemia/química , Fármacos Anti-VIH/química , Fármacos Anti-VIH/aislamiento & purificación , Línea Celular , Diterpenos/aislamiento & purificación , Humanos , Análisis Espectral/métodosRESUMEN
Two new (1 and 2) and 14 known (3-16) ingenane diterpenoids were isolated from the roots of Euphorbia ebracteolata by bioassay-guided fractionation together with UPLC-MS n analysis. The absolute configurations of the new diterpenoids were established from electronic circular dichroism (ECD) data and ECD calculations. Except for ingenol (16), the ingenane diterpenoids with long aliphatic chain substituents (1-15) exhibited potent activities against HIV-1, with IC50 values of 0.7 to 9.7 nM and selectivity index values of 96.2 to 20â¯263. From the results, it was concluded that long aliphatic chain substituents are required for the enhanced anti-HIV activity of ingenane diterpenoids.
Asunto(s)
Fármacos Anti-VIH/farmacología , Diterpenos/farmacología , Euphorbia/química , Infecciones por VIH/tratamiento farmacológico , Fármacos Anti-VIH/química , Fármacos Anti-VIH/aislamiento & purificación , Cromatografía Liquida , Diterpenos/química , Diterpenos/aislamiento & purificación , Humanos , Raíces de Plantas , Relación Estructura-ActividadRESUMEN
Two new carbazole alkaloids (1,2) and six known carbazole alkaloids (3-8) were isolated from Clausena anisum-olens. Their structures were elucidated based on extensive spectroscopic analysis. All isolated compounds (1-8) were evaluated for their anti-HIV effects on virus replication in MT-4 lymphocytes infected by HIV-1NL4-3 Nanoluc-sec virus, and new carbazole alkaloid 1 exhibited anti-HIV activity with an EC50 value of 2.4 µg/mL and SI of 7.1.
Asunto(s)
Alcaloides/farmacología , Carbazoles/farmacología , Clausena/química , VIH-1/fisiología , Alcaloides/química , Alcaloides/aislamiento & purificación , Carbazoles/química , Carbazoles/aislamiento & purificación , Línea Celular , VIH-1/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Replicación Viral/efectos de los fármacosRESUMEN
A novel cycloartane triterpenoid alkaloid, kleinhospitine E (1), six new cycloartane triterpenoids (2-7), three known cycloartane triterpenoids (8-10), and taraxerone (11) were isolated from a methanol extract of Kleinhovia hospita. Their structures were elucidated by 1D- and 2D-NMR spectroscopy as well as HRMS analysis. The absolute configurations of all isolated compounds were determined from their ECD spectra by comparison with theoretical values. Kleinhospitine E (1) is the first cycloartane alkaloid possessing an unusual γ-lactam with an oxopropylidene side chain. Compounds 2, 3, and 6 were assigned as cycloartane triterpenoids with a 9α,10α-cyclopropyl ring, which is found rarely among naturally occurring compounds, while 4 and 5 were established as isomers of compound 3 containing a 21,23-diacetal side chain. Biological evaluation revealed that compounds 4 and 9 exhibited more potent antiproliferative activities against a multidrug-resistant tumor cell line compared with its parent chemosensitive cell line. Furthermore, compound 6 exhibited submicromolar anti-HIV activity.
Asunto(s)
Malvaceae/química , Extractos Vegetales/farmacología , Triterpenos/aislamiento & purificación , Fármacos Anti-VIH/química , Fármacos Anti-VIH/aislamiento & purificación , Fármacos Anti-VIH/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Extractos Vegetales/química , Triterpenos/química , Triterpenos/farmacologíaRESUMEN
Three new compounds (1 - 3), including two euphane type triterpenes, 24,24-dimethoxy-25,26,27-trinoreuphan-3ß-ol (1) and (24S)-24-hydroperoxyeupha-8,25-dien-3ß-ol (2), and an ent-atisine diterpene, ent-atisane-3α,16α,17-triol (3), were isolated from an acetone extract of the stems of Euphorbia antiquorum, together with eight known diterpenes (4 - 11). The structures of compounds (1 - 11) were elucidated using NMR and MS spectroscopic methods. Compound 7 showed moderate activity against HIV-1 replication in vitro (EC50 = 1.38 µm).
Asunto(s)
Fármacos Anti-VIH/farmacología , Euphorbia/química , VIH-1/efectos de los fármacos , Terpenos/farmacología , Fármacos Anti-VIH/química , Fármacos Anti-VIH/aislamiento & purificación , Línea Celular Transformada , Transformación Celular Viral/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Terpenos/química , Terpenos/aislamiento & purificación , Replicación Viral/efectos de los fármacosRESUMEN
On the basis of our prior structure-activity relationship (SAR) results, our current lead optimization of 1,5-diarylanilines (DAANs) focused on the 4-substituent (R1) on the central phenyl ring as a modifiable position related simultaneously to improved drug resistance profiles and drug-like properties. Newly synthesized p-cyanovinyl-DAANs (8a-8g) with different R1 side chains plus prior active p-cyanoethyl-DAANs (4a-4c) were evaluated not only for anti-HIV potency against both wild-type HIV virus and rilpivirine-resistant (E138K, E138K+M184I) viral replication, but also for multiple drug-like properties, including aqueous solubility, lipophilicity, and metabolic stability in human liver microsomes and human plasma. This study revealed that both ester and amide R1 substituents led to low nanomolar anti-HIV potency against wild-type and rilpivirine-resistant viral strains (E138K-resistance fold changes<3). The N-substituted amide-R1 side chains were superior to ester-R1 likely due to improved aqueous solubility, lipophilicity, and higher metabolic stability in vitro. Thus, three amide-DAANs 8e, 4a, and 4b were identified with high potency against wild-type and rilpivirine-resistant viral strains and multiple desirable drug-like properties.