HIV-1 capsid (CA) plays indispensable and multiple roles in the life cycle of HIV-1, become an attractive target in antiviral therapy. Herein, we report the design, synthesis, and mechanism study of ...a novel series of dimerized phenylalanine derivatives as HIV-1 capsid inhibitors using 2-piperazineone or 2,5-piperazinedione as a linker. The structure-activity relationship (SAR) indicated that dimerized phenylalanines were more potent than monomers of the same chemotype. Further, the inclusion of fluorine substituted phenylalanine and methoxyl substituted aniline was found to be beneficial for antiviral activity. From the synthesized series, Q-c4 was found to be the most potent compound with an EC50 value of 0.57 μM, comparable to PF74. Interestingly, Q-c4 demonstrated a slightly higher affinity to the CA monomer than the CA hexamer, commensurate with its more significant effect in the late-stage of the HIV-1 lifecycle. Competitive SPR experiments with peptides from CPSF6 and NUP153 revealed that Q-c4 binds to the interprotomer pocket of hexameric CA as designed. Single-round infection assays showed that Q-c4 interferes with the HIV-1 life cycle in a dual-stage manner, affecting both pre-and post-integration. Stability assays in human plasma and human liver microsomes indicated that although Q-c4 has improved stability over PF74, this kind of inhibitor still requires further optimization. And the results of the online molinspiration software predicted that Q-c4 has desirable physicochemical properties but some properties still have some violation from the Lipinski rule of five. Overall, the dimerized phenylalanines are promising novel platforms for developing future HIV-1 CA inhibitors with considerable potential for optimization.
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•HIV-1 capsid plays indispensable roles in the life cycle of HIV-1, and becomes an attractive target in antiviral therapy.•It is imperative to explore novel HIV-1 capsid inhibitor.•Compound Q-c4 is the most potent inhibitor with an EC50 value of 0.57 μM.
Encouraged by our earlier discovery of N1-selective inhibitors, the 150-cavity of influenza virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Herein, ...we report the design, synthesis and biological evaluation of a series of novel oseltamivir derivatives via the structural modifications at C5–NH2 of oseltamivir targeting 150-cavity. Among them, compound 5c bearing 4-(3-methoxybenzyloxy)benzyl group exhibited the most potent activity, which was lower or modestly improved activities than oseltamivir carboxylate (OSC) against N1 (H1N1), N1 (H5N1) and N1 (H5N1–H274Y). Specifically, there was 30-fold loss of activity against the wild-type strain H1N1. However, 5c displayed 4.85-fold more potent activity than OSC against H5N1–H274Y NA. Also, 5c demonstrated low cytotoxicity in vitro and no acute toxicity in mice. Molecular docking studies provided insights into the high potency of 5c against N1 and N1–H274Y mutant NAs. Besides, the in silico prediction of physicochemical properties and CYP enzymatic inhibitory ability of representative compounds were conducted to evaluate their drug-like properties.
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•Novel oseltamivir derivatives via modifying C5–NH2 of oseltamivir were reported.•5c showed lower or modestly improved activities than OSC against NAs.•5c showed antiviral activities similar to those of OSC against H1N1 and H5N1.•5c demonstrated low cytotoxicity in vitro and no acute toxicity in mice.
Novel therapies are urgently needed to improve global treatment of SARS-CoV-2 infection. Herein, we briefly provide a concise report on the medicinal chemistry strategies towards the development of ...effective SARS-CoV-2 inhibitors with representative examples in different strategies from the medicinal chemistry perspective.
This review summarizes major medicinal chemistry strategies of developing SARS-CoV-2 inhibitors, including drug repositioning, large-scale screening, rational drug design based on target and utilization of natural compounds. Display omitted
Herein, we report a multi-component reaction (MCRs) to synthesise a range of 3-phenyl-5-(bromomethyl)isoxazoles analogues using DMF/water mixture as solvent, providing desired products in good to ...excellent yields. The reaction efficiently involves the 1,3-dipolar cycloaddition reaction between propargyl bromide and in situ-generated α-chloro aldoximes. The protocol proceeded well under mild metal-free conditions and showed a tolerance for a wide range of substituents.
Graphical abstract
Influenza is an acute respiratory infectious disease caused by the influenza virus, affecting people globally and causing significant social and economic losses. Due to the inevitable limitations of ...vaccines and approved drugs, there is an urgent need to discover new anti-influenza drugs with different mechanisms. The viral ribonucleoprotein complex (vRNP) plays an essential role in the life cycle of influenza viruses, representing an attractive target for drug design. In recent years, the functional area of constituent proteins in vRNP are widely used as targets for drug discovery, especially the PA endonuclease active site, the RNA-binding site of PB1, the cap-binding site of PB2 and the nuclear export signal of NP protein. Encouragingly, the PA inhibitor baloxavir has been marketed in Japan and the United States, and several drug candidates have also entered clinical trials, such as favipiravir. This article reviews the compositions and functions of the influenza virus vRNP and the research progress on vRNP inhibitors, and discusses the representative drug discovery and optimization strategies pursued.
This review summarizes compositions and functions of the influenza virus vRNP and the research progress targeting them, and discusses the representative inhibitors discovery strategies and optimization approaches pursued. Display omitted
Background
Rilpivirine (RPV) was approved by the U.S. FDA (Food and Drug Administration) in 2011 to treat individuals infected with human immunodeficiency virus 1 (HIV-1). Significantly, rilpivirine ...is three fold more potent than etravirine. Once-daily, it is used with a low oral dose (25 mg/tablet), decreasing the drug administration and bringing a better choice to the patients. However, there are many shortcomings in the existing synthesis route of RPV, such as the high cost, prolonged reaction time and low yield (18.5%).
Results
This article describes our efforts to develop an efficient and practical microwave-promoted method to synthesize rilpivirine using less toxic organic reagents and low boiling solvents. The last step's reaction time decreased from 69 h to 90 min through this optimized synthetic procedure, and the overall yield improved from 18.5 to 21%. In addition, the yield of intermediate
3
increased from 52 to 62% compared to the original patent.
Conclusion
Overall, through a series of process optimization, we have developed a practical synthesis method of rilpivirine, which is easy to scale with higher yield and shorter reaction time.
1,2,4Triazolo1,5‐apyrimidine is an important heterocyclic scaffold known to have a wide range of pharmacological activities such as anticancer, antimicrobial, anti‐tubercular, CB2 cannabinoid ...agonists, feticide, and adenosine antagonists. Several clinical trials and marketed drugs such as Trapidil, Essramycin, Pyroxsulam, DSM‐265, Flumetsulam, GNF‐6702, and Cevipabulin indicate the potential of 1,2,4triazolo1,5‐apyrimidine moiety with various functional groups in medicinal chemistry. Herein, we represent a concise report focusing on the synthetic strategies used for diversely substituted 1,2,4triazolo1,5‐apyrimidine analogs and their pharmacological applications. To the best of our knowledge, since 1980, we are the first to write a review on this emerging scaffold, which reveals the synthetic strategies, and pharmacological activities of differently substituted 1,2,4triazolo1,5‐apyrimidine with special emphasis on structure‐activity relationship studies.
Pyrazolo1,5-apyrimidine scaffold is one of the privileged hetrocycles in drug discovery. Its application as a buliding block for developing drug-like candidates has displayed broad range of medicinal ...properties such as anticancer, CNS agents, anti-infectious, anti-inflammatory, CRF1 antagonists and radio diagnostics. The structure-activity relationship (SAR) studies have acquired greater attention amid medicinal chemists, and many of the lead compounds were derived for various disease targets. However, there is plenty of room for the medicinal chemists to further exploit this privileged scaffold in developing potential drug candidates. The present review briefly outlines relevant synthetic strategies employed for pyrazolo1,5-apyrimidine derivatives. It also extensively reveals significant biological properties along with SAR studies. To the best of our understanding current review is the first attempt made towards the compilation of significant advances made on pyrazolo1,5-apyrimidines reported since 1980s.
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•Pyrazolo1,5-apyrimidine is an important and versatile scaffold in drug design and discovery.•Various synthetic approaches for the preparation of pyrazolo1,5-apyrimidine derivatives are summarized.•This review describes the chemical structures of the most active pyrazolo1,5-apyrimidine derivatives.•Review focuses on structure activity relationship (SAR) studies of pyrazolo1,5-apyrimidine scaffold.•The review shall contribute for planning research on pyrazolo1,5-apyrimidines.
1,2,4Triazolo1,5‐apyrimidine is an important heterocyclic scaffold known to have a wide range of pharmacological activities such as anticancer, antimicrobial, anti‐tubercular, CB2 cannabinoid ...agonists, feticide, and adenosine antagonists. Several clinical trials and marketed drugs such as Trapidil, Essramycin, Pyroxsulam, DSM‐265, Flumetsulam, GNF‐6702, and Cevipabulin indicate the potential of 1,2,4triazolo1,5‐apyrimidine moiety with various functional groups in medicinal chemistry. Herein, we represent a concise report focusing on the synthetic strategies used for diversely substituted 1,2,4triazolo1,5‐apyrimidine analogs and their pharmacological applications. To the best of our knowledge, since 1980, we are the first to write a review on this emerging scaffold, which reveals the synthetic strategies, and pharmacological activities of differently substituted 1,2,4triazolo1,5‐apyrimidine with special emphasis on structure‐activity relationship studies.
A capsid is the protein shell of a virus, encircling its genetic material. The HIV capsid is erected from a single protein, known as capsid protein. The capsid of HIV-1 significantly involved in many ...processes of the virus life cycle, which makes it as a novel target for the new inhibitors. Recently many novel HIV-1 inhibitors binding to capsid proteins have been reported successfully. Most of these inhibitors can inhibit or accelerate the disassembly or assembly of the capsid, and some of them can inhibit reverse transcription. Unfortunately, none of them are currently approved by U.S. FDA. However, GS-6207, an inhibitor binds to the NTD-CTD interface with potent antiviral activity and the long metabolic cycle, is expected to be the first approved drug targeting HIV-1 capsid. Herein, we provide a concise report focusing on the recent prospective of HIV-1 capsid inhibitors in medicinal chemistry in order to enlighten drug design.
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•This review introduces HIV-1 capsid as a promising drug target.•This review introduces the discovery strategies of the main CA inhibitors.•The review believes that GS-6207 is expected to be the first approved CA drug.
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