Search

HIV-1 reverse transcriptase (RT) has received great attention as an attractive therapeutic target for acquired immune deficiency syndrome (AIDS), but the inevitable drug resistance and side effects have always been major challenges faced by non-nucleoside reverse transcriptase inhibitors (NNRTIs). This work aimed to identify novel chemotypes of anti-HIV-1 agents with improved drug-resistance profiles, reduced toxicity, and excellent druggability. A series of diarylpyrimidine (DAPY) derivatives were prepared via structural modifications of the leads K-5a2 and 25a. Among them, 15a with dimethylphosphine oxide moiety showed the most prominent antiviral potency against all of the tested viral panel, being 1.6-fold (WT, EC 50 = 1.75 nmol/L), 3.0-fold (L100I, EC 50 = 2.84 nmol/L), 2.4-fold (K103N, EC 50 = 1.27 nmol/L), 3.3-fold (Y181C, EC 50 = 5.38 nmol/L), 2.9-fold (Y188L, EC 50 = 7.96 nmol/L), 2.5-fold (E138K, EC 50 = 4.28 nmol/L), 4.8-fold (F227L/V106A, EC 50 = 3.76 nmol/L) and 5.3-fold (RES056, EC 50 = 15.8 nmol/L) more effective than that of the marketed drug ETR. Molecular docking results illustrated the detailed interactions formed by compound 15a and WT, F227L/V106A, and RES056 RT. Moreover, 15a ·HCl carried outstanding pharmacokinetic (t 1/2 = 1.32 h, F = 40.8%) and safety profiles (LD 50 > 2000 mg/kg), which demonstrated that 15a HCl is a potential anti-HIV-1 drug candidate. 15a· HCl exhibited enhanced drug resistance profiles against HIV-1 mutations and possessed improved solubility, favorable pharmacokinetic and safety profiles, which suggested that 15a· HCl could be a potential anti-HIV-1 drug candidate. [Display omitted] [ABSTRACT FROM AUTHOR]

In this study, a novel series of diarylpyrimidine derivatives with Fsp3‐enriched spirocycles were designed and synthesized to further explore the chemical space of the hydrophobic channel of the NNRTI‐binding pocket. The biological evaluation results showed that most of the compounds displayed effective inhibitory potency against the HIV‐1 wild‐type strain, with EC50 values ranging from micromolar to submicromolar levels. Among them, TT6 turned out to be the most effective inhibitor with an EC50 value of 0.17 μM, demonstrating up to 47 times more active than that of reference drug 3TC (EC50 = 8.01 μM). More encouragingly, TT6 was found to potently inhibit the HIV‐1 mutant strain K103N with an EC50 value of 0.69 μM, being about 6‐fold more potent than 3TC (EC50 = 3.68 μM) and NVP (EC50 = 4.62 μM). Furthermore, TT6 exhibited the most potent inhibitory activity toward HIV‐1 reverse transcriptase with an IC50 value of 0.33 μM. Additionally, molecular simulation studies were conducted to investigate the binding modes between TT6 and NNRTI‐binding pocket, which may provide valuable clues for the follow‐up structural optimizations. [ABSTRACT FROM AUTHOR]

Non‐nucleoside reverse transcriptase inhibitors (NNRTIs) are an important component of anti‐acquired immunodeficiency syndrome treatment regimen. In the present work, with the previously reported compound K‐16c as lead, a series of novel 2,4,5‐trisubstituted pyrimidine derivatives were designed based on the cocrystal structure of K‐16c/RT, with the aim to improve the anti‐human immunodeficiency virus type‐1 (HIV‐1) activities and metabolic stability properties. Compound 11b1 exhibited the most potent antiviral activity against wild‐type (WT) and a panel of single mutant HIV‐1 strains (EC50 = 2.4−12.4 nM), being superior to or comparable to those of the approved drug etravirine. Meanwhile, 11b1 exhibited moderate cytotoxicity (CC50 = 4.96 μM) and high selectivity index (SI = 1189) toward HIV‐1 WT strain. As for HIV‐1 RT inhibition test, 11b1 possessed excellent inhibitory potency (IC50 = 0.04 μM) and confirmed its target was RT. Moreover, the molecular dynamics simulation was performed to elucidate the improved drug resistance profiles. Moreover, 11b1 was demonstrated with favorable safety profiles and pharmacokinetic properties in vivo, indicating that 11b1 is a potential anti‐HIV‐1 drug candidate worthy of further development. [ABSTRACT FROM AUTHOR]

Following on our recently developed biphenyl-ATDP non-nucleoside reverse transcriptase inhibitor ZLM-66 (SI = 2019.80, S = 1.9 μg/mL), a series of novel heterocycle-substituted ATDP derivatives with significantly improved selectivity and solubility were identified by replacement of the biphenyl moiety of ZLM-66 with heterocyclic group with lower lipophilicity. Evidently, the representative analog 7w in this series exhibited dramatically enhanced selectivity and solubility (SI = 12,497.73, S = 4472 μg/mL) in comparison with ZLM-66 (SI = 2019.80, S = 1.9 μg/mL). This new NNRTI conferred low nanomolar inhibition of wild-type HIV-1 strain and tested mutant strains (K103N, L100I, Y181C, E138K, and K103N + Y181C). The analog also demonstrated favorable safety and pharmacokinetic profiles, as evidenced by its insensitivity to CYP and hERG, lack of mortality and pathological damage, and good oral bioavailability in rats (F = 27.1%). Further development of 7w for HIV therapy will be facilitated by this valuable information. Herein, we reported the discovery of a novel series of heterocycle-substituted ATDP analogs as potent NNRTIs, of which 7w featuring dramatically enhanced selectivity and solubility compared with ZLM-66. [Display omitted] [ABSTRACT FROM AUTHOR]

Indolylarylsulfones (IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a unique scaffold and possess potent antiviral activity. To address the high cytotoxicity and improve safety profiles of IASs, we introduced various sulfonamide groups linked by alkyl diamine chain to explore the entrance channel of non-nucleoside inhibitors binding pocket. 48 compounds were designed and synthesized to evaluate their anti-HIV-1 activities and reverse transcriptase inhibition activities. Especially, compound R 10 L 4 was endowed with significant inhibitory activity towards wild-type HIV-1 (EC 50(WT) = 0.007 μmol/L, SI = 30,930) as well as a panel of single-mutant strains exemplified by L100I (EC 50 = 0.017 μmol/L, SI = 13,055), E138K (EC 50 = 0.017 μmol/L, SI = 13,123) and Y181C (EC 50 = 0.045 μmol/L, SI = 4753) which were superior to Nevirapine and Etravirine. Notably, R 10 L 4 was characterized with significantly reduced cytotoxicity (CC 50 = 216.51 μmol/L) and showed no remarkable in vivo toxic effects (acute and subacute toxicity). Moreover, the computer-based docking study was also employed to characterize the binding mode between R 10 L 4 and HIV-1 RT. Additionally, R 10 L 4 presented an acceptable pharmacokinetic profile. Collectively, these results deliver precious insights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development. R 10 L 4 exhibited significant inhibitory activity towards wild-type HIV-1 and a panel of single-mutant strains. Notably, R 10 L 4 was characterized with significantly reduced cytotoxicity and showed no remarkable in vivo toxic effects. [Display omitted] [ABSTRACT FROM AUTHOR]

This study presents proof of concept for designing a novel HIV-1 covalent inhibitor targeting the highly conserved Tyr318 in the HIV-1 non-nucleoside reverse transcriptase inhibitors binding pocket to improve the drug resistance profiles. The target inhibitor ZA-2 with a fluorosulfate warhead in the structure was found to be a potent inhibitor (EC50 = 11–246 nM) against HIV-1 IIIB and a panel of NNRTIs-resistant strains, being far superior to those of NVP and EFV. Moreover, ZA-2 was demonstrated with lower cytotoxicity (CC50 = 125 µM). In the reverse transcriptase inhibitory assay, ZA-2 exhibited an IC50 value of 0.057 µM with the ELISA method, and the MALDI-TOF MS data demonstrated the covalent binding mode of ZA-2 with the enzyme. Additionally, the molecular simulations have also demonstrated that compounds can form covalent binding to the Tyr318. [ABSTRACT FROM AUTHOR]

In this study, privileged boronic acid ester was introduced into the right wing of etravirine (ETR) to obtain a series of novel boronate-containing derivatives. These newly synthesized derivatives were evaluated for their anti-HIV potency in MT-4 cells using the MTT method, and their inhibitory activity to HIV-1 reverse transcriptase (RT) was assayed by the ELISA method. Most of the synthesized compounds displayed promising antiviral activity against the wild-type and a wide range of HIV-1 mutant strains. In particular, 4a exhibited the most potent activity against the wild-type and a panel of single mutations (L100I, K103N, Y181C, and E138K) with EC50 values ranging from 0.005 to 0.648 μM, which were much superior to those of nevirapine (EC50 = 0.151 μM). Moreover, 4b turned out to be an effective inhibitor against the double-mutant strains F227L + V106A and RES056 with EC50 values of 3.21 and 2.30 μM, respectively. RT inhibition activity and molecular docking were also investigated. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) is the primary infectious agent of acquired immunodeficiency syndrome (AIDS), and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are the cornerstone of HIV treatment. In the last 20 years, our medicinal chemistry group has made great strides in developing several distinct novel NNRTIs, including 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), thio-dihydro-alkoxy-benzyl-oxopyrimidine (S -DABO), diaryltriazine (DATA), diarylpyrimidine (DAPY) analogues, and their hybrid derivatives. Application of integrated modern medicinal strategies, including structure-based drug design, fragment-based optimization, scaffold/fragment hopping, molecular/fragment hybridization, and bioisosterism, led to the development of several highly potent analogues for further evaluations. In this paper, we review the development of NNRTIs in the last two decades using the above optimization strategies, including their structure–activity relationships, molecular modeling, and their binding modes with HIV-1 reverse transcriptase (RT). Future directions and perspectives on the design and associated challenges are also discussed. Human immunodeficiency virus (HIV) is the primary infectious agent of acquired immunodeficiency syndrome (AIDS), and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are the cornerstone of HIV treatment. In this review, we summarize the development of NNRTIs in our past two decades using the multiple optimization strategies. Image 1 [ABSTRACT FROM AUTHOR]

In this report, a series of novel piperidine-substituted thiophene[3,2- d pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket (NNIBP) by incorporating an aromatic moiety to the left wing of the lead K-5a2. The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells and inhibitory activity to HIV-1 reverse transcriptase (RT). Most of the synthesized compounds exhibited broad-spectrum activity toward wild-type and a wide range of HIV-1 strains carrying single non-nucleoside reverse transcriptase inhibitors (NNRTI)-resistant mutations. Especially, compound 26 exhibited the most potent activity against wild-type and a panel of single mutations (L100I, K103N, Y181C, Y188L and E138K) with an EC 50 ranging from 6.02 to 23.9 nmol/L, which were comparable to those of etravirine (ETR). Moreover, the RT inhibition activity, preliminary structure–activity relationship and molecular docking were also investigated. Furthermore, 26 exhibited favorable pharmacokinetics (PK) profiles and with a bioavailability of 33.8%. Taken together, the results could provide valuable insights for further optimization and compound 26 holds great promise as a potential drug candidate for the treatment of HIV-1 infection. Compound 26 exhibited potent activity against wild-type and a panel of single mutations with an EC 50 ranging from 6.02 to 23.9 nmol/L. Furthermore, 26 exhibited favorable PK profiles and with a bioavailability of 33.8%. These results demonstrated that 26 holds great promise as a potential HIV-1 drug candidate. Image 1 [ABSTRACT FROM AUTHOR]

In order to improve the positional adaptability of our previously reported naphthyl diaryltriazines (NP-DATAs), synthesis of a series of novel biphenyl-substituted diaryltriazines (BP-DATAs) with a flexible side chain attached at the C-6 position is presented. These compounds exhibited excellent potency against wild-type (WT) HIV-1 with EC 50 values ranging from 2.6 to 39 nmol/L and most of them showed low nanomolar anti-viral potency against a panel of HIV-1 mutant strains. Compounds 5j and 6k had the best activity against WT, single and double HIV-1 mutants and reverse transcriptase (RT) enzyme comparable to two reference drugs (EFV and ETR) and our lead compound NP-DATA (1). Molecular modeling disclosed that the side chain at the C-6 position of DATAs occupied the entrance channel of the HIV-1 reverse transcriptase non-nucleoside binding pocket (NNIBP) attributing to the improved activity. The preliminary structure–activity relationship and PK profiles were also discussed. This article exhibited a novel series of biphenyl-substituted diaryltriazines (BP-DATAs) as HIV-1 reverse transcriptase inhibitors targeting non-nucleoside binding pocket (NNIBP) to improve the positional adaptability. Image 1 [ABSTRACT FROM AUTHOR]

Two novel series of human immunodeficiency virus‐1 (HIV‐1) non‐nucleoside reverse transcriptase inhibitors (NNRTIs) bearing a thiophene[3,2‐d]pyrimidine scaffold and sulfonamide linker in the right wing have been identified, which demonstrated activity against the wild‐type (WT) HIV‐1 strain in MT‐4 cells with inhibitory concentrations ranging from micromolar to submicromolar. Especially, against the mutant strains K103N and E138K, most compounds exhibited more potent activity than against WT HIV‐1. Compound 7 (EC50 = 0.014, 0.031 μM) achieved the most potent activity against the two mutants, being more effective than that of nevirapine (NVP, EC50 = 7.572, 0.190 μM) and comparable to that of etravirine (ETV, EC50 = 0.004, 0.014 μM). Molecular docking experiments on the novel analogs have also suggested that the extensive network of main chain hydrogen bonds are important in the binding mode, which may provide valuable insights for further optimization. Most compounds exhibited more potent activity against the mutant strains K103N and E138K than against WT HIV‐1. Compound 7 (EC50 = 0.014, 0.031 µM) achieved the most potent activity against the two mutations, being comparable to that of ETV (EC50 = 0.004, 0.014 µM). Molecular docking experiments on the novel analogs have also suggested that the extensive network of main chain hydrogen bonds are important in the binding mode, which may provide valuable insights for further optimization. [ABSTRACT FROM AUTHOR]

In the previous studies of our laboratory, the thiophene[3,2‐d]pyrimidine was identified as a promising scaffold for seeking highly potent HIV‐1 non‐nucleoside reverse transcriptase inhibitors (NNRTIs). In this study, we designed, synthesized, and biologically evaluated a series of thiophene[3,2‐d]pyrimidine derivatives with changed linker between the thiophenepyrimidine core and the right wing. Some of the synthesized compounds exhibited excellent HIV‐1 inhibitory potency with low (double‐digit) nanomolar 50% effective concentration (EC50) values. Among them, compound 13a exhibited the most potent anti‐HIV‐1 activity (EC50 = 21.2 nM), which was 10‐fold greater than that of NVP (EC50 = 281 nM). Moreover, 13a showed much lower cytotoxicity (CC50 = 183 μM) and higher selection index (SI = 8,632) than NVP, ETV, and AZT. Besides, some physicochemical properties and water solubility were calculated or measured. The preliminary structure–activity relationships and molecular simulation studies of these compounds were also discussed comprehensively to provide valuable direction for further design and optimization. In the present study, we designed, synthesized, and biologically evaluated a series of thiophene[3,2‐d]pyrimidine derivatives bearing the hydrazone linker between the thiophenepyrimidine core and the right wing. In particular, compound 13a exhibited the most potent anti‐HIV‐1 activity. Besides, some physicochemical properties and water solubility were calculated or measured. The preliminary structure–activity relationships and molecular simulation studies of these compounds were also discussed comprehensively to provide valuable direction for further design and optimization. [ABSTRACT FROM AUTHOR]

A series of novel 5-alkyl-6-Adamantylmethylpyrimidin-4(3H)-ones bearing various substituents at the C-2 position of the pyrimidinone ring were synthesized using a facile route and evaluated for their anti- HIV activity in MT-4 cells. The biological results demonstrated that the majority of the newly designed compounds possessed moderate efficiency in inhibiting the replication of the wild-type ( WT) HIV-1 strain ( IIIB) with EC50 values in the range from 0.10 to 5.39 μ m. Among them, 5b1 and 5b3 proved to be the two most active inhibitors against WT HIV-1 with EC50 values of 0.10 and 0.12 μ m, respectively, which were more active than nevirapine ( NVP) in the same assay. In addition, HIV-1 reverse-transcriptase ( RT) inhibition assay indicated that the representative compound 5b1 showed affinity to WT HIV-1 RT, and inhibited the activity of RT with an IC50 value superior to the reference drug NVP. Moreover, the preliminary structure-activity relationship ( SAR) and the molecular modeling analysis of these new derivatives are also discussed. [ABSTRACT FROM AUTHOR]

With the continuation of our unremitting efforts toward the discovery of potent HIV-1 NNRTIs, a series of novel imidazo[4,5-b]pyridin-2-ylthioacetanilides were designed, synthesized, and evaluated for their antiviral activities through combining bioisosteric replacement and structure-based drug design. Almost all of the title compounds displayed moderate to good activities against wild-type (wt) HIV-1 strain with EC50 values ranging from 0.059 to 1.41 μ m in a cell-based antiviral assay. Thereinto, compounds 12 and 13 were the most active two analogues possessing an EC50 value of 0.059 and 0.073 μ m against wt HIV-1, respectively, which was much more effective than the control drug nevirapine (EC50 = 0.26 μ m) and comparable to delavirdine (EC50 = 0.038 μ m). In addition, one selected compound showed a remarkable reverse transcriptase inhibitory activity compared to nevirapine and etravirine. In the end of this manuscript, preliminary structure-activity relationships (SARs) and molecular modeling studies were detailedly discussed, which may provide valuable insights for further optimization. [ABSTRACT FROM AUTHOR]

We have developed a series of N2-(1-(substituted-aryl)piperidin-4-yl)-N6-mesityl-9 H-purine-2,6-diamine derivatives as potent antiviral agents. Preliminary biological evaluation indicated that nearly half of them possessed remarkable HIV inhibitory potencies in cellular assays. In particular, FZJ 13 appeared to be the most notable one, which displayed anti- HIV-1 activity compared to 3 TC. Moreover, an unexpected finding was that FZJ 05 displayed significant potency against influenza A/H1N1 (strain A/ PR/8/34) in Madin-Darby canine kidney cells with EC50 values much lower than those of ribavirin, amantadine, and rimantadine. The results suggest that these novel purine derivatives have the potential to be further developed as new therapeutic agents against HIV-1 or influenza virus. [ABSTRACT FROM AUTHOR]

A series of novel S- DABO derivatives with the substituted 1,2,3-triazole moiety on the C-2 side chain were synthesized using the simple and efficient Cu AAC reaction, and biologically evaluated as inhibitors of HIV-1. Among them, the most active HIV-1 inhibitor was 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), which exhibited similar HIV-1 inhibitory potency ( EC50 = 3.22 μ m) compared with 3 TC ( EC50 = 2.24 μ m). None of these compounds demonstrated inhibition against HIV-2 replication. The preliminary structure-activity relationship ( SAR) of these new derivatives was discussed briefly. [ABSTRACT FROM AUTHOR]

A series of benzoyl diarylamine/ether derivatives were designed, synthesized, and evaluated for their activity against human immunodeficiency virus ( HIV) in MT-4 cells. Three compounds ( 3b, 5a, and 6a1) exhibited moderate activities against wild-type (wt) HIV-1 with EC50 values ranging from 11 to 56 μ m. Among them, compound 5a was the most potent inhibitor with a novel chemical skeleton, affording a new lead compound for further molecular optimization. An enzyme assay was also implemented to confirm the binding target of the active compounds represented by 6a1. Molecular simulation studies on compound 5a, 6a1, and 7a4 were carried out to understand their binding mode with wt HIV-1 reverse transcriptase ( RT) and provided useful information for further rational design of NNRTIs. [ABSTRACT FROM AUTHOR]

Based on the hybridization of the privileged fragments in DABO and DAPY-typed HIV-1 NNRTIs, a novel series of 4-aminopiperidinyl-linked 3,5-disubstituted-1,2,6-thiadiazine-1,1-dione derivatives were designed, synthesized, and evaluated for their in vitro anti- HIV activities in MT-4 cells. Most of the target compounds showed weak inhibitory activity against WT HIV-1. In order to confirm the mode of action of the target compounds, representative compounds Ba8 and Bb8 were selected to perform the HIV-1 RT inhibitory assay. In this assay, Ba8 and Bb8 displayed good activity with IC50 values of 3.15 and 1.52 μ m, respectively. Additionally, preliminary structure-activity relationships ( SARs) analysis and molecular docking studies of newly synthesized compounds are also discussed. [ABSTRACT FROM AUTHOR]

A novel series of triazine derivatives targeting the entrance channel of the HIV-1 non-nucleoside reverse transcriptase inhibitor binding pocket (NNIBP) were designed and synthesized on the basis of our previous work. The results of a cell-based antiviral screening assay indicated that most compounds showed good-to-moderate activity against wild-type HIV-1 with EC50 values within the concentration range of 0.0078-0.16 μ m (compound DCS- a4, EC50 = 7.8 n m). Some compounds displayed submicromolar activity against the K103N/Y181C resistant mutant strain (such as compound DCS- a4, EC50 = 0.65 μ m). Molecular modeling studies confirmed that the new compounds could bind into the NNIBP similarly as the lead compound, and the newly introduced flexible heterocycles could occupy the entrance channel effectively. In addition, the preliminary structure-activity relationship and the RT inhibitory assay are presented in this study. [ABSTRACT FROM AUTHOR]

A series of 4-(naphthalen-1-yl)-1,2,5-thiadiazol-3-hydroxyl derivatives ( Ia- Im and II a- II e) designed as novel HIV-1 non-nucleoside reverse transcriptase inhibitors ( NNRTIs) was synthesized via an expeditious route and evaluated for their anti- HIV activities in MT-4 cell cultures. All the synthesized compounds were structurally confirmed by spectral analyses. Biological results showed that three analogues displayed moderate inhibitory activity against wild-type (wt) HIV-1 replication with EC50 values ranging from 16 to 22 μ m. Molecular docking of compound Ih with wt HIV-1 RT was performed to understand the binding mode between these inhibitors and the wt HIV-1 RT and to rationalize some SARs. [ABSTRACT FROM AUTHOR]

Abstract: This paper reports the synthesis and antiviral evaluation of a series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine the peculiar structural features of diarylpyrimidine derivatives (DAPYs) and benzophenone derivatives (BPs). The DAPY derivatives bearing benzoyl or alkoxyl substitutes on the A-ring showed the inhibitory activity against wild-type HIV-1 at the cellular level within the range of EC50 values from micromolar to nanomolar. Among these compounds, 1u exhibited the most potent anti-HIV-1 activity (EC50 = 0.06 ± 0.01 μM, SI > 6260), which were about 1.8-fold more active than nevirapine (NVP) and delavirdine (DLV). In addition, the binding modes with HIV-1 RT and the preliminary SAR studies of these derivatives were also considered for further investigation. [Copyright &y& Elsevier]

A series of novel N′-arylidene-2-[1-(naphthalen-1-yl)-1 H-tetrazol-5-ylthio] acetohydrazides was synthesized and evaluated, as nonnucleoside reverse transcriptase inhibitors (NNRTIs), for their in vitro HIV-1 and HIV-2 activity using the IIIB strain and ROD strain, respectively. The activity was monitored by the inhibition of the virus-induced cytopathic effect in the human T-lymphocyte (MT-4) cells. All of the new compounds were structurally confirmed by spectral analyses. Compounds 5q and 5r showed EC50 of 29.62 μM (CC50 of 169.24 ± 23.83μM) and 31.62 μM (CC50 > 309.06 μM), and resulting in selectivity index of 6 and >9, respectively. However, all newly synthesized derivatives were not active against HIV-2 replication. A series of novel N′-arylidene-2-[1-(naphthalen-1-yl)-1 H-tetrazol-5-ylthio] acetohydrazides were synthesized and evaluated for their anti-HIV activities in MT-4 cell culture. Two compounds exhibited potent inhibitory activity specifically against HIV-1 replication.[Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

A diversity of novel 2-aryl-3-heteroaryl-2-ylmethyl-1,3-thiazolidin-4-ones were designed and synthesized by reacting heteroaryl-2-ylmethyl amine with various 2,6-dihalosubstituted benzaldehydes and mercaptoacetic acid. The title compounds were evaluated for human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT) inhibitory activity. The results of in vitro assays showed that some of the compounds were effective inhibitors of HIV-1 reverse transcriptase enzyme at micromolar concentrations with less cytotoxicity in both MT-4 cells as well as acutely infected human T-lymphoid CEM cells. Compounds 4h and 4k emerged as moderately more potent with EC50 are at 0.20 and 0.21 μm as compared to reference parent compound thiazolobenzimidazoles EC50 0.35 μm in MT-4 cells. [ABSTRACT FROM AUTHOR]

Novel oxime-biphenyl-DAPYs were designed and synthesized by a privileged scaffold inspired strategy, exhibiting promising anti-HIV activity, low cytotoxicity and high selectivity index. • Fourteen oxime-biphenyl-DAPYs were designed by a privileged scaffold inspired strategy. • These compounds possessed up to nanomolar potency and low toxicity against wild-type HIV-1-infected cells. • Compound 7d displayed a high potency against WT and E138K mutant strains (EC 50 = 12.1 nM, 0.027 µM). Oxime is a key pharmacophore in drug development. The biphenyl diarylpyrimidines (DAPYs) have been developed by our group as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs). In this study, fourteen oxime-biphenyl-DAPYs were designed and synthesized through a privileged scaffold inspired design strategy. They exhibited promising activity toward wild type HIV-1 and single mutant strains. Compound 7d was found to be the most potent one against both wild type (EC 50 = 12.1 nM) and E138K mutant strains (EC 50 = 0.0270 µM). It also had a much lower cytotoxicity (CC 50 > 292 µM) and higher selective index (SI > 24105) than those of the FDA-approved drugs efavirenz and etravirine. Molecular docking and dynamics simulation predicted and disclosed the binding mode of compound 7d with the RT, providing the explanation on the antiviral activity. These results were helpful for subsequent structural optimizations in anti-HIV-1 drug discovery. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of novel HEPT analogs were designed and synthesized. • C20 conferred significantly improved potency toward WT HIV-1 (EC 50 = 0.23 μM, SI = 150.20), and was better than that of HEPT (EC 50 = 7 μM, SI = 106). • C20 was endowed with low micromolar efficacy against tested mutant strains. • Molecular docking was assayed to explain its potent biological activity. 1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymines (HEPTs) have been previously described as an important class of HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). In our continuously pursuing HEPT optimization efforts, a series of novel HEPTs, featuring –C(OH)CH 2 R, –C C, or –CHCH 2 R linker at the benzylic α-methylene unit, were developed as NNRTIs. Among these new HEPTs, the compound C20 with –CHCH 3 group at the benzylic α-methylene unit conferred the highest potency toward WT HIV-1 and selectivity (EC 50 = 0.23 μM, SI = 150.20), which was better than the lead compound HEPT (EC 50 = 7 μM, SI = 106). Also, C20 was endowed with high efficacy against clinically relevant mutant strains (EC 50(L100I) = 1.07 μM; EC 50(K103N) = 4.33 μM; EC 50(Y181C) = 5.57 μM; EC 50(E138K) = 1.06 μM; EC 50(F227L+V106A) = 5.45 μM) and wild-type HIV-1 reverse transcriptase (RT) with an IC 50 value of 0.55 μM. Molecular docking and molecular dynamics simulations, as well as preliminary structure–activity relationship (SAR) analysis of these new compounds, provided a deeper insight into the key structural features of the interactions between HEPT analogs and HIV-1 RT and laid the foundation for further modification on HEPT scaffold. [ABSTRACT FROM AUTHOR]

The hybrids of delavirdine and piperdin-4-yl-aminopyrimidine (DPAPYs) were designed from two excellent HIV-1 NNRTIs delavirdine and piperidin-4-yl-aminopyrimidine via molecular hybridization. The target compounds 4a-r were prepared and evaluated for their cellular anti-HIV activities and cytotoxicities as well as the inhibitory activities against HIV-1 reverse transcriptase (RT). All the newly synthesized compounds demonstrated moderate to excellent potency against wild-type (WT) HIV-1 with EC 50 values in a range of 5.7 to 0.0086 μM and against RT with IC 50 values ranging from 12.0 to 0.11 μM, indicating that the DPAPYs were specific RT inhibitors. Among all, 4d displayed the most potent activity against WT HIV-1 (EC 50 = 8.6 nM, SI = 2151). Gratifyingly, it exhibited good to excellent potency against the single HIV-1 mutants L100I, K103N, Y181C, Y188L, E138K, as well as the double mutant F227L + V106A. Furthermore, the preliminary structure-activity relationships were summarized, molecular modeling was conducted to explore the binding mode of DPAPYs and HIV-1 RT, and their physicochemical properties were also predicted. [Display omitted] • The hybrids of delavirdine and piperdin-4-yl-aminopyrimidine (DPAPYs) as HIV-1 NNRTIs were designed and synthesized. • The target molecules displayed moderate to excellent activities against wild-type (WT) HIV-1 with EC 50 values ranging from 5.7 to 0.0086 μM. • The compound 4d displayed the most excellent activities against WT HIV-1 (EC 50 = 8.6 nM, SI = 2151). • The compounds 4c and 4d displayed excellent activities against HIV-1 single mutant E138K with EC 50 values of 80 nM and 33 nM, respectively. [ABSTRACT FROM AUTHOR]

Adding to past success in developing non-nucleoside reverse transcriptase inhibitors (NNRTIs), we report herein our efforts to optimize an FDA-approved NNRTI, doravirine, into a series of novel biphenyl-substituted pyridone derivatives. A strategy focused on harnessing the X-ray crystal structure of doravirine, coupled with computer simulations, to guide the design of conformationally constrained analogs led to the discovery of ZLM-66 , which provided comparable inhibitory potency to doravirine against wild-type HIV-1 (EC 50 = 13 nM) and various single/double mutant strains. ZLM-66 possessed acceptable cytotoxicity and selectivity index. In vivo profiling indicated that ZLM-66 exhibited excellent pharmacokinetics with significantly improved oral bioavailability (F = 140.24%) and a more favorable half-life (T 1/2 = 8.45 h), compared to that of doravirine (F = 57%, T 1/2 = 4.4 h). In addition, ZLM-66 did not cause significant inhibition of CYP and hERG (>200 μM), as well as acute toxicity and tissue damage at a dose of 1.2 g/kg. Therefore, ZLM-66 can be used as a lead compound to further guide the development of orally active biphenyl-containing doravirine analogs for HIV therapy. [Display omitted] • Novel biphenyl-substituted pyridone derivatives were rationally designed as potent NNRTIs. • ZLM-66 displayed significant inhibitory activity against WT HIV-1 and multiple mutant strains. • ZLM-66 exhibited promising oral availability (F = 140.24%). • ZLM-66 showed almost no CYP enzyme and hERG inhibition. • No acute toxicity and pathological damage were observed at a dose of 1.2 g/kg. [ABSTRACT FROM AUTHOR]

A series of novel naphthyl-diarylpyrimidine (DAPY) derivatives were designed and synthesized to explore the entrance channel of the non-nucleoside reverse transcriptase inhibitors binding pocket (NNIBP) by incorporating different flexible side chains at the C-6 position. The biological evaluation results showed that all analogues possessed promising HIV-1 inhibitory activity at the nanomolar concentration range. Three compounds (7, 9 and 39) displayed excellent potency against WT HIV-1 strain with EC 50 values ranging from 5 to 10 nM and high selectivity indexes (SI = 3504, 30488 and 22846, respectively), which were higher than for nevirapine and comparable to the values for etravirine. The RT inhibition activity, preliminary structure-activity relationship and molecular docking study showed that the side chain at the C-6 position of the DAPYs occupied the entrance channel and significantly influenced anti-HIV activity and selectivity. Additionally, the physicochemical properties were investigated to evaluate the drug-like features, which indicated that introducing various substituents on the pyrimidine ring can improve solubility. [Display omitted] • The novel naphthyl-diarylpyrimidine derivatives were discovered by structure-based drug design. •They exhibited great anti-HIV activity and high selectivity index. •Compound 7, 9 and 39 displayed promising activity against WT strains and low cytotoxicity. •Compound 7, 9 and 39 demonstrated improved water solubility when they were prepared the salt. [ABSTRACT FROM AUTHOR]

Abstract: A novel series of piperidine-substituted triazine derivatives have been synthesized and evaluated for anti-HIV activities in MT-4 cells. Most compounds displayed extremely promising activity against wild-type HIV-1 with EC50 values in low nanomolar concentration, better than that of Nevirapine, Delavirdine, Zidovudine and Dideoxycitidine, and higher potency towards the resistant mutant strain K103N/Y181C than that of Nevirapine and Delavirdine. Selected compounds were also assayed against reverse transcriptase with lower IC50 values than that of Nevirapine. The structure-activity relationship (SAR) of these novel structural congeners was also discussed. [Copyright &y& Elsevier]

[Display omitted] • A 51-member triazole-containing diaryl-thiophene[3,2- d ]pyrimidines library was constructed by click chemistry. • 14 hits which exhibited higher or equivalent activity compared to the lead K-5a2 and ETR were identified by the in situ enzyme inhibition screening. • Compound C1N51 displayed the most potent activity (EC 50 = 0.01–0.26 μM) against wild-type and a panel of NNRTIs-resistant strains. HIV-1 reverse transcriptase (RT) is considered as one of the most significant targets for the anti-HIV-1 drug design due to their determined mechanism and well-decoded crystal structure. As a part of our continuous efforts towards the development of potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) by exploiting the tolerant region I of NNRTIs binding pocket (NNIBP), the miniaturized parallel synthesis via CuAAC click chemistry reaction followed by in situ biological screening have been performed in this work. The in situ enzyme inhibition screening results showed that 14 compounds exhibited higher or equivalent inhibitory activity compared to the lead K-5a2 and ETR. Anti-HIV-1 activity results indicated that C1N51 displayed the most potent activity (EC 50 = 0.01–0.26 μM) against wild-type and a panel of NNRTIs-resistant strains. Moreover, the molecular simulation demonstrated that the newly introduced triazole ring could develop new hydrogen bonds with Lys103 and Pro236, which explained the feasibility of introducing triazole in the tolerant region I of the RT binding pocket. [ABSTRACT FROM AUTHOR]

[Display omitted] • New 4-phenylcoumarins were synthesized as anti-HIV agents. • Compounds 8b and 4c were the most active against HIV-1 (IIIB). • Compounds 8b and 4c showed significant inhibition against HIV-1 RT. • 8b and 4c showed high docking scores against non-mutated and mutated HIV-1 RT. • Compound 8b showed a typical seahorse binding mode in HIV-1 RT pocket. A series of 4-phenylcoumarin derivatives was synthesized and evaluated for their cellular anti-HIV-1 and HIV-2 activities as well as their inhibitory effects against HIV-1 reverse transcriptase (RT). The hydrazone compound 8b and the ethylthiosemicarbazide derivative 4c showed the best inhibition activity against wild-type (WT) HIV-1. The promising compounds were further evaluated against HIV-1 RT and exhibited significant inhibitory activity with compound 8b showing comparable effect to the reference NNRTI Efavirenz (IC 50 = 9.01 nM). Structure activity relationship study revealed the importance of 6-chloro and 4-phenyl substituents for optimum activity, as well as the 5-atoms linker (=N-NH-CO-CH 2 -O-) at position 7 of coumarin scaffold that can support the rotation and flexibility of compound 8b to fit well in the binding pocket. The molecular docking of compound 8b demonstrated a typical seahorse binding mode with better binding interactions that covered more residues when compared to Efavirenz. [ABSTRACT FROM AUTHOR]

Conformational restriction is a promising strategy in the development of DAPY-type non-nucleoside reverse transcriptase inhibitors (NNRTIs). Herein, eighteen thiophene-biphenyl-DAPY derivatives were designed and synthesized as potent HIV-1 NNRTIs in which halogen and methyl groups were introduced to explore the conformationally constrained effects. Molecular docking and dynamic simulation analysis indicated that substituents on different positions of the biphenyl ring induced different dihedral angles and binding conformations, further explaining their anti-viral activities. The 2′-fluoro and 3′-chloro substitutions could form electrostatic or halogen-bonding interactions with adjacent residues of the RT enzyme. The 2′-methyl group contributed to enlarge the dihedral angle of biphenyl ring and was positioned to a space-filling hydrophobic pocket. Notably, compounds 22 and 23 with two methyl groups exhibited potent biological activity against WT HIV-1-infected MT-4 cells (EC 50 = 14 and 17 nM, respectively) and RT enzyme (EC 50 = 27 and 42 nM, respectively). In particular, 23 exhibited much lower cytotoxicity (CC 50 = 264.19 μM) and higher selectivity index (SI = 18,564) than etravirine. Taken together, a rational conformational model for further design of DAPYs is proposed, providing a new guidance for the development of NNRTIs. Image 1 • Halogen and methyl groups on the biphenyl ring lead to potential conformational preferences. • An enlarged dihedral angle of biphenyl group leads to powerful π-π interactions. • The methyl group could be positioned to a proper space-filling hydrophobic pocket. • Compound 22 with good anti-WT-HIV-1 activity maintained inhibitory ability against mutant strains and WT HIV-1 RT enzyme. [ABSTRACT FROM AUTHOR]

To develop more potent HIV-1 inhibitors against a variety of NNRTIs-resistant strains, a series of 5-cyano substituted diarylpyridines was designed based on the cocrystal structural analysis. Among them, I-5b showed the greatest potency (EC 50 = 5.62–171 nM) against the wild-type (WT) and mutant HIV-1 strains. Especially for K103 N, I-5b exhibited outstanding activity with EC 50 values of 9.37 nM, being much superior to that of NVP (EC 50 = 5128 nM) and EFV (EC 50 = 114 nM) and comparable to that of ETR (EC 50 = 3.45 nM). In addition, the target of all compounds was turned out to be HIV-1 RT with moderate RT enzyme inhibitory activity (IC 50 = 0.094–12.0 μM). Moreover, the binding mode of representative compounds with RT was elaborated via molecular docking. [Display omitted] • A series of 24 novel 5-cyano substituted diarylpyridines was designed and synthesized. • I-5b showed. • The molecular docking of representative compounds was conducted. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract A novel series of acetamide-substituted derivatives and two prodrugs of doravirine were designed and synthesized as potent HIV-1 NNRTIs by employing the structure-based drug design strategy. In MT-4 cell-based assays using the MTT method, it was found that most of the new compounds exhibited moderate to excellent inhibitory potency against the wild-type (WT) HIV-1 strain with a minimum EC 50 value of 54.8 nM. Among them, the two most potent compounds 8i (EC 50 = 59.5 nM) and 8k (EC 50 = 54.8 nM) displayed robust activity against WT HIV-1 with double-digit nanomolar EC 50 values, being superior to lamivudine (3TC, EC 50 = 12.8 μM) and comparable to doravirine (EC 50 = 13 nM). Besides, 8i and 8k shown moderate activity against the double RT mutant (K103N + Y181C) HIV-1 RES056 strain. The HIV-1 RT inhibition assay further validated the binding target. Molecular simulation of the representative compounds was employed to provide insight on their structure-activity relationships (SARs) and direct future design efforts. Finally, the aqueous solubility and chemical stability of the prodrugs 9 and 10 were investigated in detail. [ABSTRACT FROM AUTHOR]

Inspired by our previous efforts on the modifications of diarylpyrimidines as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) and reported crystallography study, novel diarylnicotinamide derivatives were designed with a “triazole tail” occupying the entrance channel in the NNRTI binding pocket of the reverse transcriptase to afford additional interactions. The newly designed compounds were then synthesized and evaluated for their anti-HIV activities in MT-4 cells. All the compounds showed excellent to good activity against wild-type HIV-1 strain with EC 50 of 0.02–1.77 μM. Evaluations of selected compounds against more drug-resistant strains showed these compounds had advantage of inhibiting E138K mutant virus which is a key drug-resistant mutant to the new generation of NNRTIs. Among this series, propionitrile ( 3b2 , EC 50(IIIB)  = 0.020 μM, EC 50(E138K)  = 0.015 μM, CC 50  = 40.15 μM), pyrrolidin-1-ylmethanone ( 3b8 , EC 50(IIIB)  = 0.020 μM, EC 50(E138K)  = 0.014 μM, CC 50  = 58.09 μM) and morpholinomethanone ( 3b9 , EC 50(IIIB)  = 0.020 μM, EC 50(E138K)  = 0.027 μM, CC 50  = 180.90 μM) derivatives are the three most promising compounds which are equally potent to the marketed drug Etravirine against E138K mutant strain but with much lower cytotoxicity. Furthermore, detailed SAR, inhibitory activity against RT and docking study of the representative compounds are also discussed. [ABSTRACT FROM AUTHOR]

By means of structure-based molecular hybridization strategy, a series of novel diarylpyri(mi)dine derivatives targeting the entrance channel of HIV-1 reverse transcriptase (RT) were designed, synthesized and evaluated as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs). Encouragingly, all the tested compounds showed good activities against wild-type (WT) HIV-1 (IIIB) with EC 50 in the range of 1.36 nM–29 nM, which is much better than those of nevirapine (NVP, EC 50  = 125.42 nM) and azidothymidine (AZT, EC 50  = 11.36 nM). Remarkably, these compounds also displayed effective activity against the most of the single and double-mutated HIV-1 strains with low EC 50 values, which is comparable to the control drugs. Besides, these compounds were also exhibited favorable enzymatic inhibitory activity. Moreover, preliminary structure-activity relationships (SARs) and molecular modeling study were investigated and discussed in detail. Unexpectedly, four diarylpyrimidines yielded moderate anti-HIV-2 activities. To our knowledge, this is rarely reported that diarylpyrimidine-based NNRTIs have potent activity against both HIV-1 and HIV-2 in cell culture. [ABSTRACT FROM AUTHOR]

As a continuation of our efforts to discover and develop “me-better” drugs of DAPYs, novel diarylpyridine derivatives were designed, synthesized and evaluated for their anti-HIV activities in MT-4 cells. The majority of these compounds showed high activity against wild-type HIV-1 strain (IIIB) with EC 50 values in the range of 0.04–4.41 μM. Among them, compound 5b2 (EC 50 = 0.04 μM, SI = 3963) was the most potent. This compound showed anti-HIV-1 IIIB activity superior than of Nevirapine but still inferior than of Etravirine. Selected compounds were also evaluated for the activity against reverse transcriptase (RT), and most of the compounds exhibited submicromolar IC 50 values indicating they are specific RT inhibitors. Preliminary structure-activity relationships and modeling studies of these new analogues provide valuable avenues for future molecular optimization. [ABSTRACT FROM AUTHOR]

A novel series of uracil-bearing DAPYs derivatives were designed and synthesized via structure-based molecular hybridization to discover compounds with improved anti-resistance profiles. Anti-HIV activity of the designed compounds was tested in MT-4 cell cultures. The most promising compound 16d showed excellent activity with EC 50 value of 5.6 nM against wide-type HIV-1 and low cytotoxicity (SI > 50000). Activity against the clinic prevalent mutant strains was also tested, suggesting that 16d was sensitive to E138K (EC 50 = 34.2 nM). Primary drug-like properties, such as water solubility and logP, were evaluated by experiment or calculation, which indicated that introducing an uracil can improve solubility. The molecular modeling accompanied with the preliminary SAR correlations paved the way for the next round of rational design of potent anti-HIV agents. [ABSTRACT FROM AUTHOR]

To further explore the chemical space around the entrance channel of HIV-1 reverse transcriptase (RT), a series of novel indolylarylsulfones (IASs) bearing N -substituted piperidine at indole-2-carboxamide were identified as potent HIV NNRTIs by structure-guided scaffold morphing and fragment rearrangement. All the IASs exhibited moderate to excellent potency against wild-type HIV-1 with EC 50 values ranging from 0.62 μM to 0.006 μM 8 (EC 50 = 6 nM) and 18 (EC 50 = 9 nM) were identified as the most potent compounds, which were more active than NVP and DLV, and reached the same order of EFV and ETV. Furthermore, most compounds maintained high activity agaist various single HIV-1 mutants (L100I, K103N, E138K, Y181C) as well as one double mutant (F227L/V106A) with EC 50 values in low-micromolar to double-digit nanomolar concentration ranges. Especially, 8 displayed outstanding potency against L100I (EC 50 = 17 nM with a 2.8-fold resistance ratio) and 18 was relatively more potent to E138K mutant (EC 50 = 43 nM with a 4.7-fold resistance ratio). Preliminary SARs and molecular modelin g studies were also discussed in detail, which may provide valuable insights for further optimization. [ABSTRACT FROM AUTHOR]

Here, we reported a novel series of "dual-site" binding diarylpyrimidine (DAPY) derivatives targeting both the NNRTI adjacent site and NNRTIs binding pocket (NNIBP). The anti-HIV-1 activity results demonstrated that compound 9e (EC 50 = 2.04–61.1 nM) displayed robust potencies against a panel of HIV-1 NNRTIs-resistant strains, being comparable to that of etravirine (ETR). Moreover, 9e displayed much lower cytotoxicity (CC 50 = 59.2 μM) and higher SI values (4605) toward wild-type HIV-1 strain. The HIV-1 RT enzyme inhibitory activity clarified the binding target of 9e was HIV-1 RT (IC 50 = 0.019 μM). Furthermore, the molecular modeling study was also investigated to give a reasonable explanation of the preliminary SARs. Further test indicated that 9e possessed significantly improved water solubility under pH 7.0 and 7.4 conditions. Additionally, the in silico prediction of physicochemical properties and CYP enzymatic inhibitory ability were investigated to evaluate their drug-like features. Consequently, compound 9e showed the highest activity and low cytotoxicity, which could be used as a lead for further modification to obtain potent HIV-1 NNRTIs. [Display omitted] • A series of "dual-site" binding diarylpyrimidine derivatives were discovered. • Acetylene group was introduced for the first time to specifically target the "NNRTI Adjacent" binding site. • 9e showed promising activity against the wild-type and mutant strains of HIV-1. • The preliminary SARs based on antiviral activity was analyzed in detail. [ABSTRACT FROM AUTHOR]

Following on our initial discovery of S -CN-DABOs as non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel S -N 3 -DABO derivatives F1-F31 were developed by substituting the cyano group of S -CN-DABOs with azide group. Some of these compounds were conferred significantly increased potency against wild-type HIV-1 and clinically observed mutant strains. Remarkably, the best compound F10 exerted a 7-fold improvement in potency (EC 50 = 0.053 μM) and 12.5-fold higher selectivity (SI = 6818) in MT-4 cells infected with wild-type HIV-1, compared to that of the parent compound B1 (EC 50 = 370 nM, SI = 547). The anti-HIV-1 activity of F10 against the tested mutant strains was prominently enhanced. For wild-type reverse transcriptase, it was approximately 19-fold more potent (IC 50 = 0.080 μM) than B1 (IC 50 = 1.51 μM). It was not found that this analog had significant inhibition of hERG, CYP, and acute toxicity after a single dose of F10 (1.0 g/kg). [Display omitted] • A novel series of S -N 3 -DABOs were developed as potent NNRTIs. • F10 exerted 7-fold improvement in potency (EC 50 = 0.053 μM) and 12.5-fold higher selectivity (SI = 6818), compared to B1. • The anti-resistance activity of F10 was prominently enhanced. • This analog had no significant inhibition of hERG, CYP, and acute toxicity. [ABSTRACT FROM AUTHOR]

Herein, via crystallographic overlay-based molecular hybridization strategy, a series of disubstituted pyrimidine-5-carboxamide derivatives were designed by introducing an amide moiety to the central core of the lead etravirine. All the newly synthesized compounds were evaluated for their anti-HIV-1 potencies in MT-4 cells using the MTT method. Most of the synthesized compounds displayed promising antiviral activities against the wild-type (IIIB) and a panel of HIV-1 NNRTIs-resistant strains. Especially, 21c exhibited the most potent activity (EC 50 = 0.009–0.065 μM) against HIV-1 IIIB, L100I, K103N, Y181C, Y188L, and RES056, being comparable to those of etravirine. The inhibitory activity to reverse transcriptase (RT) was evaluated by ELISA method, and the target of the compounds was proved to be RT. Moreover, the molecular docking was investigated to clarify the binding mode of 21c with RT. Overall, the results demonstrated that 21c could serve as a lead for further modification to develop novel HIV-1 NNRTIs. [Display omitted] • A series of disubstituted pyrimidine-5-carboxamides were designed and synthesized. • Crystallographic overlay-based molecular hybridization strategy was utilized. • The amide moiety was introduced to the central core of the lead etravirine. • 21c showed promising activity against the wild-type and mutant strains of HIV-1. • The preliminary SARs based on antiviral activity was analyzed in detail. [ABSTRACT FROM AUTHOR]

By means of structure-based bioisosterism approach, a series of novel purinylthioacetanilide derivatives were designed, synthesized and evaluated as potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Some of the tested compounds were found to be active against wild-type (WT) HIV-1(IIIB) with EC 50 in the range of 0.78–4.46 μM. Among them, LAD-8 displayed the most potent anti-HIV activity (EC 50 = 0.78 μM, SI = 24). In addition, LBD-6 showed moderate activity against L100I mutant (EC 50 = 5.64 μM) and double mutant strain RES056 (EC 50 = 22.24 μM). Preliminary structure–activity relationships (SARs) were discussed in detail. Molecular modeling study was used to predict the optimal conformation in the NNRTI binding site, which may play a guiding role in further rational optimization. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of novel sulfinyl-substituted HEPT analogs were designed by a structure-based design strategy. • 11l displayed potent inhibitory activity against WT HIV-1, mutant strains L100I and E138K, and RT. • 11l exhibited acceptable cytotoxicity and selectivity. • Molecular modeling studies were performed to elucidate their potent biological activity. The [(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) analogs were reported to be a kind of promising lead compounds as nonnucleoside HIV-1 reverse transcriptase inhibitors. In this work, a series of novel sulfinyl-substituted analogs were designed by structure-based design strategy with the purpose of improving the activity of HEPT, followed by evaluating their anti-HIV-1 activity in MT-4 cells. Most of the final compounds had moderate to strong activity against wild-type HIV-1 strain (III B) with EC 50 values in the range of 0.21–1.91 μM, which were around 4 ∼ 32-fold better than the reference compound HEPT. Some of them showed higher sensitivity toward clinically relevant mutant L100I and E138K viruses than NVP. Selected compounds were further evaluated for their activity against wild-type reverse transcriptase (RT), and most of them exhibited nanomolar activity, suggesting a good correlation with the cell-based activity. The compounds 11h , 11l , and 11ab displayed the best anti-HIV-1 activity against wild-type HIV-1 strain (EC 50 = 0.280, 0.209, and 0.290 μM) and nanomolar activity against mutant strains (L100I and E138K), superior to HEPT and NVP. Molecular modeling studies were also performed to elucidate the biological activity, providing a structural insight for follow-up research on HEPT optimization. [ABSTRACT FROM AUTHOR]

A series of 1,6-bis[(benzyloxy)methyl]uracil derivatives combining structural features of both diphenyl ether and pyridone types of NNRTIs were synthesized. Target compounds were found to inhibit HIV-1 reverse transcriptase at micro- and submicromolar levels of concentrations and exhibited anti-HIV-1 activity in MT-4 cell culture, demonstrating resistance profile similar to first generation NNRTIs. The synthesized compounds also showed profound activity against influenza virus (H1N1) in MDCK cell culture without detectable cytotoxicity. The lead compound of this assay appeared to exceed rimantadine, amantadine, ribavirin and oseltamivir carboxylate in activity. The mechanism of action of 1,6-bis[(benzyloxy)methyl]uracils against influenza virus is currently under investigation. [ABSTRACT FROM AUTHOR]

The development of novel NNRTIs with activity against variants of HIV-1RT is crucial for overcoming treatment failure. In the present study, a series of novel 6-substituted diarylpyridine derivatives targeting the entrance channel of the NNIBP of RT were designed through a molecular hybridization strategy. Encouragingly, these new diarylpyridine derivatives were found to be active against wild-type (WT) HIV-1 with an EC50 values ranging from 0.035 μM to 1.99 μM. Nearly half of them exhibited more potent inhibitory activities in cellular assays than the control drug nevirapine (NVP). Notably, three most promising compounds If (EC50 = 35 nM), Ia (EC50 = 43 nM) and IIa (EC50 = 41 nM) showed high potency against WT and were comparable to the reference drug delavirdine (DLV) (EC50 = 33 nM). Moreover, compounds Ib , IIb and IIh displayed effective activity against the most common clinically observed single and double-mutated HIV-1 strains in micromolar concentrations. In particular, the inhibition of IIb against the K103N mutation (EC50 = 49 nM), which confers resistance to a wide variety of NNRTIs, was about 140 times more effective than NVP (EC50 = 6.78 μM), 50 times more than DLV (EC50 = 2.48 μM) and about 3 times more than EFV (EC50 = 0.12 μM), indicating that the newly designed compounds have great potential to be further developed as new anti-HIV-1 agents. Preliminary structure-activity relationships (SARs) and molecular modeling of the new diarylpyridine derivatives were discussed in detail. [ABSTRACT FROM AUTHOR]