Non-peptidic inhibitors targeting SARS-CoV-2 main protease: A review.

The COVID-19 pandemic continues to pose a threat to global health, and sounds the alarm for research & development of effective anti-coronavirus drugs, which are crucial for the patients and urgently needed for the current epidemic and future crisis. The main protease (Mpro) stands as an essential enzyme in the maturation process of SARS-CoV-2, playing an irreplaceable role in regulating viral RNA replication and transcription. It has emerged as an ideal target for developing antiviral agents against SARS-CoV-2 due to its high conservation and the absence of homologous proteases in the human body. Among the SARS-CoV-2 Mpro inhibitors, non-peptidic compounds hold promising prospects owing to their excellent antiviral activity and improved metabolic stability. In this review, we offer an overview of research progress concerning non-peptidic SARS-CoV-2 Mpro inhibitors since 2020. The efforts delved into molecular structures, structure-activity relationships (SARs), biological activity, and binding modes of these inhibitors with Mpro. This review aims to provide valuable clues and insights for the development of anti-SARS-CoV-2 agents as well as broad-spectrum coronavirus Mpro inhibitors.

Quinolines and isoquinolines as HIV-1 inhibitors: Chemical structures, action targets, and biological activities.

Human immunodeficiency virus type 1 (HIV-1), a lentivirus that causes acquired immunodeficiency syndrome (AIDS), poses a serious threat to global public health. Since the advent of the first drug zidovudine, a number of anti-HIV agents acting on different targets have been approved to combat HIV/AIDS. Among the abundant heterocyclic families, quinoline and isoquinoline moieties are recognized as promising scaffolds for HIV inhibition. This review intends to highlight the advances in diverse chemical structures and abundant biological activity of quinolines and isoquinolines as anti-HIV agents acting on different targets, which aims to provide useful references and inspirations to design and develop novel HIV inhibitors for medicinal chemists.

Indole derivatives as tubulin polymerization inhibitors for the development of promising anticancer agents.

The α- and ß-tubulins are the major polypeptide components of microtubules (MTs), which are attractive targets for anticancer drug development. Indole derivatives display a variety of biological activities including antitumor activity. In recent years, a great number of indole derivatives as tubulin polymerization inhibitors have sprung up, which encourages medicinal chemists to pursue promising inhibitors with improved antitumor activities, excellent physicochemical, pharmacokinetic and pharmacodynamic properties. In this review, the recent progress from 2010 to present in the development of indole derivatives as tubulin polymerization inhibitors was summarized and reviewed, which would provide useful clues and inspirations for further design of outstanding tubulin polymerization inhibitors.

Free Amino Acid Recognition: A Bisbinaphthyl-Based Fluorescent Probe with High Enantioselectivity.

A novel fluorescent probe based on a bisbinaphthyl structure has been designed and synthesized. This compound in combination with Zn(II) has exhibited highly enantioselective fluorescence enhancement with 13 common free amino acids. For example, its enantiomeric fluorescent enhancement ratios ( ef or Δ IL/Δ ID) in the presence of the following amino acids are extremely high: 177 for valine, 199 for methionine, 186 for phenylalanine, 118 for leucine, and 89 for alanine. The observed high enantioselectivity and the extent of the substrate scope are unprecedented in the fluorescent recognition of free amino acids. This fluorescent probe can be applied to determine the enantiomeric composition of the structurally diverse chiral amino acids. NMR and mass spectroscopic investigations have provided clues to elucidate the observed high enantioselectivity.

Biphasic Enantioselective Fluorescent Recognition of Amino Acids by a Fluorophilic Probe.

A fluorophilic fluorescent probe based on a perfluoroalkyl-substituted bis(binaphthyl) compound was designed and synthesized. It displayed a highly enantioselective fluorescence response toward structurally diverse amino acids in a biphasic fluorous/aqueous system with enantiomeric fluorescent enhancement ratio (ef; ΔID /ΔIL ) values up to 45.2 (histidine). It can be used to determine the enantiomeric compositions of amino acids and also allows the amino acid enantiomers to be visually discriminated. NMR and mass-spectroscopic investigations provided insights into the observed high enantioselectivity. This biphasic fluorescent recognition was used to determine the enantiomeric composition of the crude phenylalanine products generated by an enzyme-catalyzed asymmetric hydrolysis under various reaction conditions. The fluorous-phase-based fluorescence measurement under the biphasic conditions was able to minimize the interference of other reaction components and thus has potential in asymmetric reaction screening.

Design and synthesis of hybrids of diarylpyrimidines and diketo acids as HIV-1 inhibitors.

Based on the strategy of molecular hybridization, diketo acid fragment as a classical phamacophore of integrase inhibitors was introduced to reverse transcriptase inhibitors diarylpyrimidines to design a series of diarylpyrimidine-diketo acid hybrids (DAPY-DKAs). The target molecules 10b and 11b showed inhibitory activities against WT HIV-1 with EC50 values of 0.18µM and 0.14µM, respectively. And the results of molecular docking demonstrated the potential binding mode and revealed that the DKA moiety and its ester could both be tolerated in the nonnucleoside binding site (NNBS) of HIV-1 RT.

Structural modifications of diarylpyrimidines (DAPYs) as HIV-1 NNRTIs: Synthesis, anti-HIV activities and SAR.

30 new analogues of diarylpyrimidines were synthesized for further structural modifications, involving not only the linker but also the wing α of DAPYs. The anti-HIV-1 activities of all target molecules were evaluated, and most of them exhibited potent anti-HIV-1 (WT) activities and low cytotoxicities. Among which, compound 4g showed excellent activities against WT HIV-1 with an EC50 value of 5.8nM and SI of up to 26,034. Another compound 4ab bearing a novel pyridinyl Wing α also displayed attractive activities. The structure-activity relationship (SAR) study was also summarized.

Advances in rationally designed dual inhibitors of HIV-1 reverse transcriptase and integrase.

Reverse transcriptase (RT) and integrase (IN) are two indispensable enzymes in human immunodeficiency virus type 1 (HIV-1) replication. RT is responsible for the transformation of the single-stranded RNA viral genome into double-stranded DNA, and IN catalyzes the integration of viral DNA into the host DNA. Although highly active antiretroviral therapy (HAART) combining nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) with nonnucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs) could suppress successfully HIV viral load and reduce evidently the mortality of HIV infected people, it involves the difficulty of perfect adherence, and other drawbacks such as viral rebound, toxicities and multi-drug resistances. Recently, rational drug design has become a dominant technique for the development of multi-target drugs. And the rationally designed dual inhibitors of HIV-1 RT and IN have become a hot topic of anti-HIV research. In this review, the advances in rationally designed dual inhibitors of HIV-1 RT and IN were summarized, including structurally diverse inhibitors, their structure-activity relationship (SAR) studies as well as binding mode analysis.

A novel family of diarylpyrimidines (DAPYs) featuring a diatomic linker: Design, synthesis and anti-HIV activities.

To improve the conformational flexibility and positional adaptability of the traditional diarylpyrimidines (DAPYs), a family of diarylpyrimidines featuring a C-N diatomic linker between the left wing benzene ring and the central pyrimidine was firstly designed, synthesized, and evaluated for in vitro anti-HIV activity. Most of target molecules showed excellent activities against wild-type (WT) HIV-1. Among them the most potent two compounds 12h and 12r displayed extremely potent WT HIV-1 inhibitory activities with an EC50 of 2.6 nM and 3.0 nM, respectively, while their selective index (CC50/EC50) values were both over 1000. Another compound 12b (EC50 14.9 nM) was also noteworthy due to its high SI of 18,614. Moreover, all of compounds were evaluated for their WT HIV-1 reverse transcriptase activities, which shown that the newly synthesized CH2NH-DAPYs bind to HIV-1 RT and belong to the genuine NNRTIs. However, the synthesized compounds lack the activities against HIV-1 double mutant (RES056) and HIV-2 (ROD). Thus it is an upcoming objective to improve the activities against HIV-1 double mutants.

T7 peptide-mediated co-delivery platform overcoming multidrug-resistant breast cancer: In vitro and in vivo evaluation.

P-glycoprotein (P-gp) overexpressed mutidrug resistance (MDR) is currently a key factor limiting the effectiveness of breast cancer chemotherapy. Systemic administration based on P-gp-associated mechanism leads to severe toxic side effects. Here, we designed a T7 peptide-modified mixed liposome (T7-MLP@DTX/SchB) that, by active targeting co-delivering chemotherapeutic agents and P-gp inhibitors, harnessed synergistic effects to improve the treatment of MDR breast cancer. This study established drug-resistant cell models and animal models. Subsequently, comprehensive evaluations involving cell uptake, cell apoptosis, cellular toxicity assays, in vivo tumor-targeting capability, and anti-tumor activity assays were conducted to assess the drug resistance reversal effects of T7-MLP@DTX/SchB. Additionally, a systematic assessment of the biosafety profile of T7-MLP@DTX/SchB was executed, including blood profiles, biochemical markers, and histopathological examination. It was found that this co-delivery strategy successfully exerted the synergistic effects, since there was a significant tumor growth inhibitory effect on multidrug-resistant breast cancer. Targeted modification with T7 peptide enhanced the therapeutic efficacy remarkably, while vastly ameliorating the biocompatibility compared to free drugs. The intriguing results supported the promising potential use of T7-MLP@DTX/SchB in overcoming MDR breast cancer treatment.

E3 ligase ligand optimization of Clinical PROTACs.

Proteolysis targeting chimeras (PROTACs) technology can realize the development of drugs for non-druggable targets that are difficult to achieve with traditional small molecules, and therefore has attracted extensive attention from both academia and industry. Up to now, there are more than 600 known E3 ubiquitin ligases with different structures and functions, but only a few have developed corresponding E3 ubiquitin ligase ligands, and the ligands used to design PROTAC molecules are limited to a few types such as VHL (Von-Hippel-Lindau), CRBN (Cereblon), MDM2 (Mouse Doubleminute 2 homolog), IAP (Inhibitor of apoptosis proteins), etc. Most of the PROTAC molecules that have entered clinical trials were developed based on CRBN ligands, and only DT2216 was based on VHL ligand. Obviously, the structural optimization of E3 ubiquitin ligase ligands plays an instrumental role in PROTAC technology from bench to bedside. In this review, we review the structure optimization process of E3 ubiquitin ligase ligands currently entering clinical trials on PROTAC molecules, summarize some characteristics of these ligands in terms of druggability, and provide some preliminary insights into their structural optimization. We hope that this review will help medicinal chemists to develop more druggable molecules into clinical studies and to realize the greater therapeutic potential of PROTAC technology.

Iridium-Catalyzed Intramolecular Asymmetric Allylation of Vinyl Benzoxazinones for the Synthesis of Chiral 4H-3,1-Benzoxazines via Kinetic Resolution.

Chiral benzoxazinones and 4H-3,1-benzoxazines as important motifs are widely found in abundant pharmaceuticals and biological molecules. We herein successfully developed the first kinetic resolution (KR) process of racemic benzoxazinones through Ir-catalyzed asymmetric intramolecular allylation, furnishing a wide range of chiral benzoxazinones and 4H-3,1-benzoxazines with excellent results via outstanding KR performances (with the s factor up to 170). This protocol exhibited broad substrate scope generality and good functional group tolerance, and the chiral 4H-3,1-benzoxazine products could be readily transformed to other useful optically active heterocycles.

Hybrids of delavirdine and piperdin-4-yl-aminopyrimidines (DPAPYs) as potent HIV-1 NNRTIs: Design, synthesis and biological activities.

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 EC50 values in a range of 5.7 to 0.0086 µM and against RT with IC50 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 (EC50 = 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.

A naphthimide-based ratiometric fluorescent probe for selective and visual detection of phosgene in solution and the gas phase.

As a colorless, highly toxic and widely used chemical reagent, phosgene poses a potentially serious threat to public health and environmental safety. Therefore, there is an urgent need to develop a simple and sensitive method for detecting phosgene. In this work, a ratiometric fluorescent probe (NED) for phosgene was developed by utilizing 4-substituted 1,8-naphthimide unit as the fluorophore and ethylenediamine as the recognition moiety. The probe NED undergoes intramolecular cyclization reaction with phosgene, resulting in a remarkable ratiometric fluorescence response. The probe NED displays high sensitivity (LOD = 4.9 nM), excellent ratiometric fluorescence signal, and high selectivity toward phosgene over other relevant analytes. In addition, paper test strip capable of visually detecting gaseous phosgene has also been fabricated.

Synthesis and structure-activity relationship of novel diarylpyrimidines with hydromethyl linker (CH(OH)-DAPYs) as HIV-1 NNRTIs.

A series of 26 diarylpyrimidines, characterized by the hydroxymethyl linker between the left wing benzene ring and the central pyrimidine, were synthesized and evaluated for in vitro anti-HIV activity. Most of the compounds exhibited moderate to excellent activities against wild-type HIV-1. Among them, compound 10i, bearing a chlorine atom at the C-2 position of left benzene ring, was the best congener and showed potent activity against wild-type HIV-1 with an EC(50) value of 0.009 µM, along with moderate activities against the double RT mutant (K103N+Y181C) HIV-1(III(B)) and HIV-2(ROD) with an EC(50) value of 6.2 and 6.0 µM, respectively. The preliminary structure-activity relationship (SAR) of this new series of compounds was also investigated.

Structural modifications of quinolone-3-carboxylic acids with anti-HIV activity.

A series of new quinolone-3-carboxylic acids featuring a hydroxyl group at C-5 position were synthesized and evaluated for their in vitro activity against HIV in C8166 cell culture. All the compounds showed anti-HIV-1 activity with low micromolar to submicromolar EC(50) values. The most active compound 2k exhibited activity against wild-type HIV-1 with an EC(50) value of 0.13 µΜ. Preliminary structure-activity relationship of the newly synthesized quinolone analogues was also investigated. Further docking study revealed that the anti-HIV activity of these compounds might involve a two-metal chelating mechanism.

Synthesis and biological evaluation of naphthyl phenyl ethers (NPEs) as novel nonnucleoside HIV-1 reverse transcriptase inhibitors.

A novel series of naphthyl phenyl ether analogues (NPEs) have been synthesized and evaluated for their in vitro activities against HIV in C8166 cells. Most of the compounds exhibited moderate to excellent anti-HIV activities. Among them the most active compound 12o showed excellent activities against wild-type HIV-1 with an EC(50) value of 4.60 nM, along with moderate activities against the double mutant strain HIV-1(IIIB) A17 (K103N+Y181C) and HIV-2 strain ROD with an EC(50) value of 0.82 and 4.40 µM, respectively. Preliminary structure-activity relationship (SAR) among the newly synthesized NPEs was also investigated.

Synthesis and biological activity of naphthyl-substituted (B-ring) benzophenone derivatives as novel non-nucleoside HIV-1 reverse transcriptase inhibitors.

A novel series of benzophenone derivatives with B-ring substituted by naphthyl ring has been synthesized and evaluated as non-nucleoside HIV-1 reverse transcriptase inhibitors. Most of these compounds showed good to moderate activity against wild-type HIV-1 and mutated viruses. In particular, the analogue 10i demonstrated the most potent activity against wild-type HIV-1 with an EC50 value of 4.8 nM, and with a high selectivity index up to 10347.9, it also proved to be active against the HIV-1 double mutant strain A17 (K103N+Y181C) with an EC50 value of 2.1 µM. In addition, the molecular modeling study was used to explore the major interactions between the potent inhibitors with the HIV-1 RT. The investigation of the structure-activity relationships may serve as an important lead for the further optimization.

Synthesis and biological evaluation of HQCAs with aryl or benzyl substituents on N-1 position as potential HIV-1 integrase inhibitors.

A series of new 5-hydroxylquinolone-3-carboxylic acids (HQCAs) with various aryl or benzyl substituents on N-1 position were synthesized and evaluated for their anti-HIV activity in C8166 cell culture. Most of the target compounds displayed activity against wide-type HIV-1 in the low micromolar range in infected C8166 cells. The most active compound 5 g exhibited activity against wild-type HIV-1 and HIV-1 mutant virus A17 with an EC(50) value of 3.17 and 17.88 µM, respectively. The biological results and the docking study revealed that the substitution pattern on N-1 position of the quinolone core might contribute to physicochemical properties of HQCAs and resulted in great influence on their antiviral potency.

Synthesis and biological evaluation of (±)-benzhydrol derivatives as potent non-nucleoside HIV-1 reverse transcriptase inhibitors.

A series of (±)-benzhydrol derivatives featuring the essential sulfonamide group at the para position on the C-ring were synthesized and evaluated for the potential anti-HIV activity in C8166 cells. Most of these analogues demonstrated low concentration inhibitory activity with EC(50) values less than 1 µM against the wild-type HIV-1. In particular, compound 7h was identified as the highest active inhibitor of wild-type HIV-1 with an EC(50) value of 0.12 µM and selectivity index value of 312.73. Furthermore, some of them also exhibited moderate activity against the double mutant strain A(17) (K103N+Y181C) with EC(50) values lower than 5 µM. In addition, the binding modes with RT and the preliminary structure-activity relationships of these derivatives were also explored for further chemical modifications.