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In addressing the urgent need for novel HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) to combat drug resistance, we employed CuAAC click chemistry to construct a diverse 312-member diarylpyrimidine (DAPY) derivative library. This rapid synthesis approach facilitated the identification of A6N36 , demonstrating exceptional HIV-1 RT inhibitory activity. Moreover, it was demonstrated with EC 50 values of 1.8–8.7 nM for mutant strains L100I, K103 N, Y181C, and E138K, being equipotent or superior to that of ETR. However, A6N36 's efficacy was compromised against specific resistant strains (Y188L, F227L + V106A and RES056), highlighting a need for further optimization. Through scaffold hopping, we optimized this lead to develop 10c , which exhibited broad-spectrum activity with EC 50 values ranging from 3.2 to 57.5 nM and superior water solubility. Molecular docking underscored the key interactions of 10c within the NNIBP. Our findings present 10c as a promising NNRTI lead, illustrating the power of click chemistry and rational design in combatting HIV-1 resistance. [Display omitted] • CuAAC click chemistry was employed to construct a diverse 312-member diarylpyrimidine (DAPY) derivative library. • 10c demonstrated promising antiviral activity against both IIIB strain and mutant strains of HIV-1. • 10c displayed significantly improved water solubility compared with ETR and RPV. • Molecular modeling studies of 10c with NNIBP provided insights into the mechanisms of drug resistance. [ABSTRACT FROM AUTHOR]

[Display omitted] • Passerini-3CR and Ugi-4CR proved to be an effective strategy for constructing multifunctional anti-AD agents. • Target compounds could be multifunctional anti-AD agents based on oxidative stress processes. • A3B3C1 exhibited versatility in antioxidant, Aβ 1-42 reduction and neuroprotection, which is deserve further development. As Alzheimer's disease (AD) is a neurodegenerative disease with a complex pathogenesis, the exploration of multi-target drugs may be an effective strategy for AD treatment. Multifunctional small molecular agents can be obtained by connecting two or more active drugs or privileged pharmacophores by multicomponent reactions (MCRs). In this paper, two series of polysubstituted pyrazine derivatives with multifunctional moieties were designed as anti-AD agents and synthesized by Passerini-3CR and Ugi-4CR. Since the oxidative stress plays an important role in the pathological process of AD, the antioxidant activities of the newly synthesized compounds were first evaluated. Subsequently, selected active compounds were further screened in a series of AD-related bioassays, including Aβ 1-42 self-aggregation and deaggregation, BACE-1 inhibition, metal chelation, and protection of SH-SY5Y cells from H 2 O 2 -induced oxidative damage. Compound A3B3C1 represented the best one with multifunctional potencies. Mechanism study showed that A3B3C1 acted on Nrf2/ARE signaling pathway, thus increasing the expression of related antioxidant proteins NQO1 and HO-1 to normal cell level. Furthermore, A3B3C1 showed good in vitro human plasma and liver microsome stability, indicating a potential for further development as multifunctional anti-AD agent. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • BChE is considered a promising drug target for the treatment of moderate to severe Alzheimer's disease. • The development of selective BChE inhibitors will move on from trial-and-error approaches to increasingly sophisticated strategies. • The insightful application of critical molecular design elements is a very effective strategy to improve the success rates of target-based drug discovery. • New medicinal chemistry concepts and techniques can be utilized for the discovery of novel and selective BChE inhibitors. Butyrylcholinesterase (BChE) is considered a promising drug target for the treatment of moderate to severe Alzheimer's disease (AD). Here, we review medicinal-chemistry strategies that are currently available for the discovery of selective BChE inhibitors. [ABSTRACT FROM AUTHOR]

Cell division cycle 25 (Cdc25) protein phosphatases play key roles in the transition between the cell cycle phases and their association with various cancers has been widely proven, which makes them ideal targets for anti-cancer treatment. Though several Cdc25 inhibitors have been developed, most of them displayed low activity and poor subtype selectivity. Therefore, it is extremely important to discover novel small molecule inhibitors with potent activities and significant selectivity for Cdc25 subtypes, not only served as drugs to treat cancer but also to probe its mechanism in transitions. In this study, miniaturized parallel click chemistry synthesis via CuAAC reaction followed by in situ biological screening were used to discover selective Cdc25 inhibitors. The bioassay results showed that compound M2N12 proved to be the most potent Cdc25 inhibitor, which also act as a highly selective Cdc25C inhibitor and was about 9-fold potent than that of NSC 663284. Moreover, M2N12 showed remarkable anti-growth activity against the KB-VIN cell line, equivalent to that of PXL and NSC 663284. An all-atom molecular dynamics (MD) simulation approach was further employed to probe the significant selectivity of M2N12 for Cdc25C relative to its structural homologs Cdc25A and Cdc25B. Overall, above results make M2N12 a promising lead compound for further investigation and structural modification. Image 1 • 96 quinone derivatives were synthesized via miniaturized click-chemistry reaction. • M2N12 is a potent and selective Cdc25C inhibitor. • M2N12 showed significant anti-tumor activity against cancer cells. • The selectivity of M2N12 for Cdc25C was rationalized by MD simulation. [ABSTRACT FROM AUTHOR]

• Drug-likeness refers to the similarity between compounds and drugs; drug-like compounds are more likely to be transformed into drugs. • Chemical structures with enhanced 3D shape have achieved great attention to medicinal chemists. • Fsp3 can predict molecular properties and contribute to the discovery of new drugs. • Spirocycles will become a significant part of sp3-rich scaffolds. The drug-likeness of a compound is a key factor during the initial phases of drug discovery. It can be defined as the similarity between compounds and drugs. Here, we collate research related to the fraction of sp3 carbon atoms (Fsp3), including related high-throughput screening (HTS) cases, structural modifications based on Fsp3, and strategies to improve it. We also introduce new synthetic methods for spirocyclic scaffolds. It is likely that the reasonable rigidity of spirocyclic scaffolds will provide a new generation of drug candidates. During the drug discovery phase, the mean Fsp3 rises from 0.36 for 2.2 million molecules to 0.47 for 1179 approved drugs, indicating that it is feasible to use Fsp3 to evaluate the drug-likeness of compounds. [ABSTRACT FROM AUTHOR]

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-4 cells. Eight compounds exhibited moderate to excellent potencies in inhibiting wild-type (WT) HIV-1 replication with EC 50 values ranging from 2.45 nM to 5.36 nM, and 14c (EC 50 = 2.45 nM) proved to be the most promising inhibitor. Of note, 14c exhibited potent activity against the single mutant strain E138K (EC 50 = 10.6 nM), being comparable with ETR (EC 50 = 9.80 nM) and 3.5-fold more potent than that of compound 7 (EC 50 = 37.3 nM). Moreover, 14c acted as a classical NNRTI with high affinity for WT HIV-1 RT (IC 50 = 0.0589 μM). 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. Image 1 • A series of "dual-site" binding diarylpyrimidine derivatives were discovered. • Trans -double bond with spatial orientation advantage was introduced. • 14c turned out to be potent inhibitor against single mutation strain E138K. • 14c acted as classical NNRT inhibitors with high affinity for WT HIV-1 RT. • 14c and 17l are proposed as promising inhibitors by MD simulation. [ABSTRACT FROM AUTHOR]

HIV-1 RT has been considered as one of the most important targets for the development of anti-HIV-1 drugs for their well-solved three-dimensional structure and well-known mechanism of action. In this study, with HIV-1 RT as target, we used miniaturized parallel click chemistry synthesis via CuAAC reaction followed by in situ biological screening to discover novel potent HIV-1 NNRTIs. A 156 triazole-containing inhibitor library was assembled in microtiter plates and in millimolar scale. The enzyme inhibition screening results showed that 22 compounds exhibited improved inhibitory activity. Anti-HIV-1 activity results demonstrated that A3N19 effected the most potent activity against HIV-1 IIIB (EC 50 = 3.28 nM) and mutant strain RES056 (EC 50 = 481 nM). The molecular simulation analysis suggested that the hydrogen bonding interactions of A3N19 with the main chain of Lys101 and Lys104 was responsible for its potency. Overall, the results indicated the in situ click chemistry-based strategy was rational and might be amenable for the future discovery of more potent HIV-1 NNRTIs. Image 1 • Rapid assembly and in situ screening of focused combinatorial fragment libraries using CuAAC chemistry was used to discover HIV-1 NNRTIs for the first time. • 22 compounds were identified as anti-HIV-1 hits in the in situ RT screening. • A3N19 (EC 50 = 3.28 nM, SI > 64103) exhibited potent activity than ETR (EC 50 = 5.1 nM, SI > 889) against HIV-1 IIIB. [ABSTRACT FROM AUTHOR]

A series of Ebselen derivatives with improve activity and selectivity were discovered by introducing privilege groups that reported to be preferred by SARS-CoV-2 Mpro active site. [Display omitted] • We discover 24 novel Ebselen derivatives as SARS-CoV-2 Mpro inhibitors. • 3a inhibits SARS-CoV-2 replication in Vero-E6 cells with low micromolar activity. • Novel Ebselen derivatives are covalent SARS-CoV-2 Mpro inhibitors. • 10f selectively inhibits Mpro without inhibiting human cysteine proteases cathepsin B and cathepsin K. The main protease (Mpro) represents one of the most effective and attractive targets for designing anti-SARS-CoV-2 drugs. In this study, we designed and synthesized a novel series of Ebselen derivatives by incorporating privileged fragments from different pockets of the Mpro active site. Among these compounds, 11 compounds showed submicromolar activity in the FRET-based SARS-CoV-2 Mpro inhibition assay, with IC 50 values ranging from 233 nM to 550 nM. Notably, compound 3a displayed submicromolar Mpro activity (IC 50 = 364 nM) and low micromolar antiviral activity (EC 50 = 8.01 µM), comparable to that of Ebselen (IC 50 = 339 nM, EC 50 = 3.78 µM). Time-dependent inhibition assay confirmed that these compounds acted as covalent inhibitors. Taken together, our optimization campaigns thoroughly explored the structural diversity of Ebselen and verified the impact of specific modifications on potency against Mpro. [ABSTRACT FROM AUTHOR]

Abstract The HIV-1 capsid (CA) protein plays essential roles in both early and late stages of HIV-1 replication and is considered an important, clinically unexploited therapeutic target. As such, small drug-like molecules that inhibit this critical HIV-1 protein have become a priority for several groups. Therefore, in this study we explore small molecule targeting of the CA protein, and in particular a very attractive inter-protomer pocket. We report the design, parallel synthesis, and anti-HIV-1 activity evaluation of a series of novel phenylalanine derivatives as HIV-1 CA protein inhibitors synthesized via Cu(I)-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC) reaction. We demonstrate robust inhibitory activity over a range of potencies against the HIV-1 NL 4-3 reference strain. In particular, compound 13m exhibited the greatest potency and lowest toxicity within this new series with an EC 50 value of 4.33 μM and CC 50 value of >57.74 μM (SI > 13.33). These values are very similar to the lead compound PF-74 (EC 50 = 5.95 μM, CC 50 > 70.50 μM, SI > 11.85) in our assay, despite significant structural difference. Furthermore, we demonstrate via surface plasmon resonance (SPR) binding assays that 13m interacts robustly with recombinant HIV-1 CA and exhibits antiviral activity in both the early and late stages of HIV-1 replication. Overall, the novel parallel synthesis and structure-activity relationships (SARs) identified within this study set the foundation for further rational optimization and discovery of CA-targeting compounds with improved potency. Graphical abstract Image 1 Highlights • 20 new compounds designed and synthesized using a parallel "click" chemistry approach. • Most potent new compounds are equipotent to PF-74 in assay utilized. • New compounds retain binding specificity to HIV-1 CA. • Most potent compound inhibits HIV-1 in both early and late stages of replication. [ABSTRACT FROM AUTHOR]