Diarylpyrimidine Derivatives Research Articles

Identification of novel diarylpyrimidine derivatives as potent HIV-1 non-nucleoside reverse transcriptase inhibitors against wild-type and K103N mutant viruses

HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) play a crucial role in combination antiretroviral therapy (cART). To further enhance their antiviral activity and anti-resistance properties, we developed a series of novel NNRTIs, by specifically targeting tolerant region I of the NNRTI binding pocket. Among them, compound 9t-2 displayed excellent anti-HIV-1 potency against wild-type and prevalent mutant strains with EC50 values between 0.0019 and 0.012 μM. This outperformed the positive drugs ETR, NVP and RPV. Aslo, ELISA results confirmed that these compounds can effectively inhibit the activity of HIV-1 RT. Molecular dynamics (MD) simulation studies indicated that the thiomorpholine-1,1-dioxide moiety of 9t-2 is capable of establishing additional interactions with residues P225, F227 and P236 in the tolerant region I, which contributed to its enhanced activity. Compound 9t-2 possessed negligible inhibitory effect on the five main CYP isoenzymes (IC50 > 10 μM), indicating a low potential for inducing CYP-mediated drug-drug interactions. In conclusion, compound 9t-2, with its enhanced anti-resistance properties, stands out as a promising lead compound for further optimization towards discovering the new generation of anti-HIV agents.

Design and optimization of piperidine-substituted thiophene[3,2-d]pyrimidine-based HIV-1 NNRTIs with improved drug resistance and pharmacokinetic profiles

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, EC50 = 1.75 nmol/L), 3.0-fold (L100I, EC50 = 2.84 nmol/L), 2.4-fold (K103N, EC50 = 1.27 nmol/L), 3.3-fold (Y181C, EC50 = 5.38 nmol/L), 2.9-fold (Y188L, EC50 = 7.96 nmol/L), 2.5-fold (E138K, EC50 = 4.28 nmol/L), 4.8-fold (F227L/V106A, EC50 = 3.76 nmol/L) and 5.3-fold (RES056, EC50 = 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 (t1/2 = 1.32 h, F = 40.8%) and safety profiles (LD50 > 2000 mg/kg), which demonstrated that 15a HCl is a potential anti-HIV-1 drug candidate.

Design and synthesis of Fsp3-enriched spirocyclic-substituted diarylpyrimidine derivatives as novel HIV-1 NNRTIs.

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.

Design, synthesis, and bioevaluation of diarylpyrimidine derivatives as novel microtubule destabilizers.

In this work, a series of new diarylpyrimidine derivatives as microtubule destabilizers were designed, synthesized, and evaluated for anticancer activities. Based on restriction configuration strategy, we introduced the pyrimidine moiety containing the hydrogen-bond acceptors as cis-olefin bond of CA-4 analogs to improve structural stability. Compounds 11a-t exerted antiproliferative activities against three human cancer cell lines (SGC-7901, HeLa, and MCF-7), due to tubulin polymerization inhibition, showing high selectivity toward cancer cells in comparison with non-tumoral HSF cells, as evidenced by MTT assays. In mechanistic investigations, compound 11s remarkably inhibited tubulin polymerization and disorganized microtubule in SGC-7901 cells by binding to tubulin. Moreover, 11s caused G2/M phase cell cycle arrest in SGC-7901 cells in a concentration-dependent manner. Furthermore, molecular modeling analysis revealed that 11s interacts with tubulin through binding to the colchicine site. In addition, the prediction of physicochemical properties disclosed that 11s conformed well to the Lipinski's rule of five. This work offered a fresh viewpoint for the discovery of new tubulin-targeting anticancer drugs.

Discovery of diarylpyrimidine derivatives bearing piperazine sulfonyl as potent HIV-1 nonnucleoside reverse transcriptase inhibitors

HIV-1 reverse transcriptase is one of the most attractive targets for the treatment of AIDS. However, the rapid emergence of drug-resistant strains and unsatisfactory drug-like properties seriously limit the clinical application of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Here we show that a series of piperazine sulfonyl-bearing diarylpyrimidine-based NNRTIs were designed to improve the potency against wild-type and NNRTI-resistant strains by enhancing backbone-binding interactions. Among them, compound 18b1 demonstrates single-digit nanomolar potency against the wild-type and five mutant HIV-1 strains, which is significantly better than the approved drug etravirine. The co-crystal structure analysis and molecular dynamics simulation studies were conducted to explain the broad-spectrum inhibitory activity of 18b1 against reverse transcriptase variants. Besides, compound 18b1 demonstrates improved water solubility, cytochrome P450 liability, and other pharmacokinetic properties compared to the currently approved diarylpyrimidine (DAPY) NNRTIs. Therefore, we consider compound 18b1 a potential lead compound worthy of further study.

Identification of “dual-site”-binding diarylpyrimidines targeting both NNIBP and the NNRTI adjacent site of the HIV-1 reverse transcriptase

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 (EC50 = 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 (CC50 = 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 (IC50 = 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.

Lead Optimization and Avoidance of Metabolic-perturbing Motif Developing Novel Diarylpyrimidines as Potent HIV-1 NNRTIs.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent an indispensable part of anti-HIV-1 therapy. To discover novel HIV-1 NNRTIs with increased drug resistance profiles and improved pharmacokinetic (PK) properties, a series of novel diarylpyrimidine derivatives were generated via the cocrystal structure-based drug design strategy. Among them, 36a exhibited outstanding antiviral activity against HIV-1 IIIB and a panel of mutant strains (L100I, K103N, Y181C, Y188L, E138K, F227L + V106A, and RES056), with EC50 ranging from 2.22 to 53.3 nM. Besides, 36a was identified with higher binding affinity (KD = 2.50 μM) and inhibitory activity (IC50 = 0.03 μM) to HIV-1 RT. Molecular docking and molecular dynamics simulation were performed to rationalize the design and the improved drug resistance of these novel inhibitors. Additionally, 36a·HCl exhibited favorable PK (T1/2 = 5.12 h, F = 12.1%) and safety properties (LD50 > 2000 mg/kg). All these suggested that 36a·HCl may serve as a novel drug candidate anti-HIV-1 therapy.

Molecular Modeling and Docking Studies of 2,4,5-Trisubstituted Pyrimidines as HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

Human immunodeficiency virus (HIV) reverse transcriptase (RT) works in the life cycle of HIV and is one of the key targets for anti-HIV-1 drug development. Recently, a novel series of diarylpyrimidine derivatives (DAPYs) have been reported as potent HIV-1 non-nucleoside RT inhibitors (NNRTIs), and they exhibit potent antiviral activity. Here we explored the binding interaction patterns of a set of 2,4,5-trisubstituted pyrimidine derivatives using molecular docking, three-dimensional quantitative structure–activity relationships (3D-QSAR), and molecular dynamics (MD) simulations. Molecular docking for exploring the mechanism of action of small molecule ligands with receptor proteins. Comparative molecular field (CoMFA q 2 = 0.828, r 2 = 0.988, r 2 pred = 0.981) and comparative molecular similarity index (CoMSIA q2 = 0.859, r 2 = 0.968, r 2 pred = 0.980) were performed to build stable and reliable 3D-QSAR models. The contour plots revealed the relationship between structural features and inhibitory activities. Based on the molecular docking analysis and contour maps, some novel compounds with higher predicted activities were designed and further MD simulations and bind free energy calculations were performed. Our models results may provide an essential reference for the design and development of effective novel HIV-1 NNRTIs.

Identification of Boronate-Containing Diarylpyrimidine Derivatives as Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors.

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.

Synthesis, Molecular Docking and Biological Evaluation of Diaryl Pyrimidine Derivatives as Urease Inhibitors

Synthesis, Molecular Docking and Biological Evaluation of Diaryl Pyrimidine Derivatives as Urease Inhibitors

Molecular Docking Structure-Activity Relationship, ADMET Evaluation and Pharmacokinetics Studies of Anti-HIV Agents and Methyl-Diarylpyrimidines Non-Nucleoside Reverse Transcriptase Inhibitors

In this study, the interaction between human immunodeficiency virus reverse transcriptase and methyldiarylpyrimidines containing a hydroxyimino, hydrazine, hydroxyl, cyclopropylamino, cyano or chloro etc. substituent was studied by molecular docking simulation, molecular docking was accomplished with AutoDock4.2 and absorption, distribution, metabolism, excretion and toxicity-structure-activity relationship and Swiss absorption, distribution, metabolism and excretion servers were used to predict the pharmacokinetics and absorption, distribution, metabolism, excretion and toxicity properties of all compounds. As a result, molecular docking analysis revealed that there are extensive interactions between the diarylpyrimidine derivatives and Lys101, Tyr188, Val179, Lys103, Glu138, Leu234, Phe227 and Trp229 residues in the active site of human immunodeficiency virus-1 reverse transcriptase. The formation of hydrogen bonds between diarylpyrimidines and the residues Lys101 and Glu138 play important roles in inhibiting the activity of human immunodeficiency virus. All compounds respect the conditions mentioned in Lipinski’s rule and have acceptable absorption, distribution, metabolism, excretion and toxicity properties. The preliminary structure-activity relationship was also investigated. A preliminary structureactivity relationship analysis of these target molecules highlighted a preference for the smaller or more flexible group’s substitution in the linker between the left ring and the pyrimidine skeleton for enhancing the anti-human immunodeficiency virus-1 activity. The acrylonitrile C4-substituent substantially improved the potency against wild-type human immunodeficiency virus-1 and several mutant strains, and the 2nd position is the most preferred position to improve antiviral activity. This information might be helpful for further diarylpyrimidine optimizations.

Docking, ADMET prediction, DFT analysis, synthesis, cytotoxicity, antibacterial screening and QSAR analysis of diarylpyrimidine derivatives

A new series of 2, 4 disubstituted diarylpyrimidine derivatives has been designed, synthesized and screened for their antibacterial activity. QSAR studies followed by antibacterial screening using broth dilution technique showed excellent MIC values against four human pathogens, namely Escherichia coli, Pseudomonas aeruginosa, Bacillus cerus and Staphylococcus aureus. Some molecules were found to be highly active (MIC value up to 3.1 µg/mL) against different types of human pathogens, like P. aeruginosa, E. coli, S. aureus and B. cerus. All compounds having MIC values greater than reference drugs were subjected for combinatorial antibacterial screening with chloramphenicol, cycloheximide and paromomycin as standard references and fractional inhibitory concentration (FIC) values of compounds exhibited great synergistic effect as their MIC values were lowered by 1/33, 1/16 and 1/8 of the original MIC's. In vitro evaluation of cytotoxicity indicates that these molecules were less toxic against HEK293 (Human embryonic kidney) cell lines. Molecular docking assessment also revealed that all designed 2,4 disubstituted diarylpyrimidine derivatives showed good interaction within active site of PDF enzyme (PDB ID: 1G2A). 2, 4 disubstituted diarylpyrimidines formed H-bond with amino acid residue Leu91, Arg97, Ile44, Ile94, Gly89 and Glu95 at a distance of 2.78 - 3.20 Å. Molecules also showed π - + and π – π interaction with amino acid residues Arg97 and His132. In silico assessment of all molecules exhibited more than 88% of intestinal absorption, which was higher than the reference antibiotics viz. chloramphenicol (69.94%), cycloheximide (74.26%) and paromomycin (76.46%).

Design, synthesis and anti-HIV evaluation of novel 5-substituted diarylpyrimidine derivatives as potent HIV-1 NNRTIs

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are widely used in combination therapies against HIV-1. As a continuation of our efforts to discover and develop “me-better” drugs of DAPYs, novel diarylpyrimidine derivatives were designed, synthesized and evaluated for their anti-HIV activities in MT-4 cells. All the compounds demonstrated strong inhibition activity against wide-type HIV-1 strain (IIIB) with EC50 values in the range of 2.5 nM ~ 0.93 μM. Among them, compounds IVB-5–4 and IVB-5–8 were the most potent ones which showed anti-HIV-1IIIB activity much superior than that of Nevirapine, comparable to Efavirenz and Etravirine. What’s more, some compounds also showed low nanomole activity against some mutant strains such as K103N and E138K. The selected compound IVB-5–4 was also evaluated for the activity against reverse transcriptase (RT), and exhibited submicromolar IC50 values indicating that this series compounds are specific RT inhibitors. Preliminary structure–activity relationships and modeling studies of these new analogues provide valuable avenues for future molecular optimization.

Boronic acid-containing diarylpyrimidine derivatives as novel HIV-1 NNRTIs: Design, synthesis and biological evaluation

Drug resistance remains to be a serious problem with type I human immunodeficiency virus (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs). A series of novel boronic acid-containing diarylpyrimidine (DAPY) derivatives were designed via bioisosterism and scaffold-hopping strategies, taking advantage of the ability of a boronic acid group to form multiple hydrogen bonds. The target compounds were synthesized and evaluated for their anti-HIV activities and cytotoxicity in MT-4 cells. Compound 10j yielded the most potent activity and turned out to be a single-digit nanomolar inhibitor towards the HIV-1 IIIB [wild-type (WT) strain], L100I and K103N strains, with 50% effective concentration (EC50) values of 7.19–9.85 nmol/L. Moreover, 10j inhibited the double-mutant strain RES056 with an EC50 value of 77.9 nmol/L, which was 3.3-more potent than that of EFV (EC50 = 260 nmol/L) and comparable to that of ETR (EC50 = 32.2 nmol/L). 10j acted like classical NNRTIs with high affinity for WT HIV-1 reverse transcriptase (RT) with 50% inhibition concentration (IC50) value of 0.1837 μmol/L. Furthermore, molecular dynamics simulation indicated that 10j was proposed as a promising molecule for fighting against HIV-1 infection through inhibiting RT activity. Overall, the results demonstrated that 10j could serve as a lead molecule for further modification to address virus-drug resistance.

Design, synthesis, and evaluation of "dual-site"-binding diarylpyrimidines targeting both NNIBP and the NNRTI adjacent site of the HIV-1 reverse transcriptase.

Inspired by our previous efforts to improve the drug-resistance profiles of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a novel series of "dual-site" binding diarylpyrimidine (DAPY) derivatives targeting both the NNRTI adjacent site and NNRTIs binding pocket (NNIBP) were designed, synthesized, and evaluated for their anti-HIV potency in TZM-bl and MT-4cells. Eight compounds exhibited moderate to excellent potencies in inhibiting wild-type (WT) HIV-1 replication with EC50 values ranging from 2.45nM to 5.36nM, and 14c (EC50=2.45nM) proved to be the most promising inhibitor. Of note, 14c exhibited potent activity against the single mutant strain E138K (EC50=10.6nM), being comparable with ETR (EC50=9.80nM) and 3.5-fold more potent than that of compound 7 (EC50=37.3nM). Moreover, 14c acted as a classical NNRTI with high affinity for WT HIV-1 RT (IC50=0.0589μM). The detailed structure-activity relationships (SARs) of the representative compounds were also determined, and further supported by molecular dynamics simulation. Overall, we envision that the "dual-site"-binding NNRTIs have significant prospects and pave the way for the next round of rational design of potent anti-HIV-1 agents.

Exploiting the tolerant region I of the non-nucleoside reverse transcriptase inhibitor (NNRTI) binding pocket. Part 2: Discovery of diarylpyrimidine derivatives as potent HIV-1 NNRTIs with high Fsp3 values and favorable drug-like properties.

To yield potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with favorable drug-like properties, a series of novel diarylpyrimidine derivatives targeting the tolerant region I of the NNRTI binding pocket were designed, synthesized and biologically evaluated. The most active inhibitor 10c exhibited outstanding antiviral activity against most of the viral panel, being about 2-fold (wild-type, EC50=0.0021μM), 1.7-fold (K103N, EC50=0.0019μM), and slightly more potent (E138K, EC50=0.0075μM) than the NNRTI drug etravirine (ETR). Additionally, 10c was endowed with relatively low cytotoxicity (CC50=18.52μM). More importantly, 10c possessed improved drug-like properties compared to those of ETR with an increased Fsp3 (Fraction of sp3 carbon atoms) value. Furthermore, the molecular dynamics simulation and molecular docking studies were implemented to reveal the binding mode of 10c in the binding pocket. Taken together, 10c is a promising lead compound that is worth further investigation.

Targeting virus–host interaction by novel pyrimidine derivative: an in silico approach towards discovery of potential drug against COVID-19

The entire human population over the globe is currently facing appalling conditions due to the spread of infection from coronavirus disease-2019 (COVID-19). The spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) present on the surface of the virion mediates the virus entry into the host cells and therefore is targeted by several scientific groups as a novel drug target site. The spike glycoprotein binds to the human angiotensin-converting enzyme-2 (hACE2) cell surface receptor abundantly expressed in lung tissues, and this binding phenomenon is a primary determinant of cell tropism and pathogenesis. The binding and internalization of the virus is the primary and most crucial step in the process of infection, and therefore the molecules targeting the inhibition of this process certainly hold a significant therapeutic value. Thus, we systematically applied the computational techniques to identify the plausible inhibitor from a chosen set of well characterized diaryl pyrimidine analogues which may disrupt interfacial interaction of spike glycoprotein (S) at the surface of hACE2. Using molecular docking, molecular dynamics (MD) simulation and binding free energy calculation, we have identified AP-NP (2-(2-amino-5-(naphthalen-2-yl)pyrimidin-4-yl)phenol), AP-3-OMe-Ph (2-(2-amino-5-(3-methoxyphenyl)pyrimidin-4-yl)phenol) and AP-4-Me-Ph (2-(2-amino-5-(p-tolyl) pyrimidin-4-yl)phenol) from a group of diaryl pyrimidine derivatives which appears to bind at the interface of the hACE2-S complex with low binding free energy. Thus, pyrimidine derivative AP-NP may be explored as an effective inhibitor for hACE2-S complex. Furthermore, in vitro and in vivo studies will strengthen the use of these inhibitors as suitable drug candidates against SARS-COV-2. Communicated by Ramaswamy H. Sarma

Anti-HIV potential of diarylpyrimidine derivatives as non-nucleoside reverse transcriptase inhibitors: design, synthesis, docking, TOPKAT analysis and molecular dynamics simulations

In view of the low toxicity of NNRTIs in comparison to NRTIs, a new series of diarylpyrimidine derivatives has been designed as NNRTIs against HIV-1. In silico studies using DS 3.0 software have shown that these compounds behaved as NNRTIs while interacting at the allosteric site of HIV-RT. The designed compounds have shown promising docking results, which revealed that all compounds formed hydrogen bonds with Lys101, Lys103, Tyr181, Tyr318 and π- interactions with Tyr181, Tyr188, Phe227 and Trp229 amino acid residues located in the non-nucleoside inhibitor binding pocket (NNIBP) of HIV-RT protein. The intended molecules have shown high binding affinity with HIV-1 RT, analogous to standard drug molecule—etravirine. TOPKAT results confirmed that the designed compounds were found to be less toxic than the reference drug. Further, employing molecular dynamics simulations, the complexes of the best screened compound 6 and etravirine with the HIV-1 RT protein were analyzed by calculating the RMSD, RMSF, R g, number of hydrogen bonds, principal components of the coordinates, molecular mechanics-Poisson-Boltzmann surface area-based binding free energy and their decomposition for different interactions. The analysis demonstrated the higher stability of compound 6 than the standard drug etravirine with HIV-1 RT. The interactions like hydrogen-bonding, van-der-Waals, electrostatic and the solvent accessible surface energy have favorable contributions to the complex stability. Thus, the shortlisted designed compound has great promise as a potential inhibitor against HIV-1 RT.

Discovery and Characterization of Fluorine-Substituted Diarylpyrimidine Derivatives as Novel HIV-1 NNRTIs with Highly Improved Resistance Profiles and Low Activity for the hERG Ion Channel.

Our previous efforts have led to the development of two potent NNRTIs, K-5a2 and 25a, exhibiting effective anti-HIV-1 potency and resistance profiles compared with etravirine. However, both inhibitors suffered from potent hERG inhibition and short half-life. In this article, with K-5a2 and etravirine as leads, series of novel fluorine-substituted diarylpyrimidine derivatives were designed via molecular hybridization and bioisosterism strategies. The results indicated 24b was the most active inhibitor, exhibiting broad-spectrum activity (EC50 = 3.60-21.5 nM) against resistant strains, significantly lower cytotoxicity (CC50= 155 μM), and reduced hERG inhibition (IC50 > 30 μM). Crystallographic studies confirmed the binding of 24b and the role of the fluorine atom, as well as optimal contacts of a nitrile group with the main-chain carbonyl group of H235. Furthermore, 24b showed longer half-life and favorable safety properties. All the results demonstrated that 24b has significant promise in circumventing drug resistance as an anti-HIV-1 candidate.

Exploiting the Tolerant Region I of the Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Binding Pocket: Discovery of Potent Diarylpyrimidine-Typed HIV-1 NNRTIs against Wild-Type and E138K Mutant Virus with Significantly Improved Water Solubility and Favorable Safety Profiles.

Diarylpyrimidine derivatives (DAPYs) exhibit robust anti-HIV-1 potency, although they have been compromised by E138K variant and severe side-effects and been suffering from poor water solubility. In the present work, hydrophilic morpholine or methylsulfonyl and sulfamide-substituted piperazine/piperidines were introduced into the right wing of DAPYs targeting the solvent-exposed tolerant region I. The anti-HIV-1 activities of 11c (EC50(WT) = 0.0035 μM, EC50(E138K) = 0.0075 μM) were the same as and 2-fold better than that of the lead etravirine against the wild-type and E138K mutant HIV-1, respectively, with a relative low cytotoxicity (CC50 ≥ 173 μM). Further test showed a significant improvement in the water solubility of 11c. Besides, 11c displayed no significant inhibition on main cytochrome P450 enzymes and exhibited no acute/subacute toxicities at doses of 2000 mg·kg-1/50 mg·kg-1 in mice. Taken together, we consider that 11c is a promising lead for further structural optimization.