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1.
Sci Rep ; 12(1): 13880, 2022 08 16.
Article in English | MEDLINE | ID: covidwho-1991664

ABSTRACT

A series of 1″-(alkylsulfonyl)-dispiro[indoline-3,2'-pyrrolidine-3',3″-piperidine]-2,4″-diones 6a‒o has been synthesized through regioselective multi-component azomethine dipolar cycloaddition reaction of 1-(alkylsulfonyl)-3,5-bis(ylidene)-piperidin-4-ones 3a‒h. X-ray diffraction studies (6b‒d,h) confirmed the structures. The majority of the synthesized analogs reveal promising antiproliferation properties against a variety of human cancer cell lines (MCF7, HCT116, A431 and PaCa2) with good selectivity index towards normal cell (RPE1). Some of the synthesized agents exhibit potent inhibitory properties against the tested cell lines with higher efficacies than the standard references (sunitinib and 5-fluorouracil). Compound 6m is the most potent. Multi-targeted inhibitory properties against EGFR and VEGFR-2 have been observed for the synthesized agents. Flow cytometry supports the antiproliferation properties and shows the tested agents as apoptosis and necrosis forming. Vero cell viral infection model demonstrates the anti-SARS-CoV-2 properties of the synthesized agents. Compound 6f is the most promising (about 3.3 and 4.8 times the potency of the standard references, chloroquine and hydroxychloroquine). QSAR models explain and support the observed biological properties.


Subject(s)
Antineoplastic Agents , COVID-19 , Spiro Compounds , Antineoplastic Agents/chemistry , COVID-19/drug therapy , Cell Line, Tumor , Humans , Indoles , Molecular Structure , SARS-CoV-2 , Spiro Compounds/chemistry , Spiro Compounds/pharmacology
2.
Sci Adv ; 6(28): eabb8097, 2020 07.
Article in English | MEDLINE | ID: covidwho-1388430

ABSTRACT

The prevalence of respiratory illness caused by the novel SARS-CoV-2 virus associated with multiple organ failures is spreading rapidly because of its contagious human-to-human transmission and inadequate globalhealth care systems. Pharmaceutical repurposing, an effective drug development technique using existing drugs, could shorten development time and reduce costs compared to those of de novo drug discovery. We carried out virtual screening of antiviral compounds targeting the spike glycoprotein (S), main protease (Mpro), and the SARS-CoV-2 receptor binding domain (RBD)-angiotensin-converting enzyme 2 (ACE2) complex of SARS-CoV-2. PC786, an antiviral polymerase inhibitor, showed enhanced binding affinity to all the targets. Furthermore, the postfusion conformation of the trimeric S protein RBD with ACE2 revealed conformational changes associated with PC786 drug binding. Exploiting immunoinformatics to identify T cell and B cell epitopes could guide future experimental studies with a higher probability of discovering appropriate vaccine candidates with fewer experiments and higher reliability.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/immunology , Coronavirus Infections/prevention & control , Cysteine Endopeptidases/chemistry , Drug Design , Pandemics/prevention & control , Peptidyl-Dipeptidase A/chemistry , Pneumonia, Viral/prevention & control , Spike Glycoprotein, Coronavirus/chemistry , Viral Nonstructural Proteins/chemistry , Angiotensin-Converting Enzyme 2 , Benzamides , Benzazepines , Betacoronavirus/drug effects , Betacoronavirus/metabolism , Binding Sites , COVID-19 , Coronavirus 3C Proteases , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cysteine Endopeptidases/immunology , Cysteine Endopeptidases/metabolism , Drug Evaluation, Preclinical , Epitopes, B-Lymphocyte/drug effects , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/drug effects , Epitopes, T-Lymphocyte/immunology , Humans , Molecular Docking Simulation , Peptidyl-Dipeptidase A/immunology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Protein Binding , Protein Conformation , Protein Domains , Protein Interaction Domains and Motifs , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Spiro Compounds/pharmacology , Viral Nonstructural Proteins/immunology , Viral Nonstructural Proteins/metabolism
3.
Eur J Med Chem ; 211: 113014, 2021 Feb 05.
Article in English | MEDLINE | ID: covidwho-918799

ABSTRACT

Viruses are obligate intracellular parasites and have evolved to enter the host cell. To gain access they come into contact with the host cell through an initial adhesion, and some viruses from different genus may use heparan sulfate proteoglycans for it. The successful inhibition of this early event of the infection by synthetic molecules has always been an attractive target for medicinal chemists. Numerous reports have yielded insights into the function of compounds based on the dispirotripiperazine scaffold. Analysis suggests that this is a structural requirement for inhibiting the interactions between viruses and cell-surface heparan sulfate proteoglycans, thus preventing virus entry and replication. This review summarizes our current knowledge about the early history of development, synthesis, structure-activity relationships and antiviral evaluation of dispirotripiperazine-based compounds and where they are going in the future.


Subject(s)
Antiviral Agents/pharmacology , Drug Design , Piperazines/pharmacology , Spiro Compounds/pharmacology , Viruses/drug effects , Antiviral Agents/chemistry , Heparan Sulfate Proteoglycans/antagonists & inhibitors , Heparan Sulfate Proteoglycans/metabolism , Molecular Structure , Piperazines/chemistry , Spiro Compounds/chemistry , Viruses/metabolism
4.
Int J Mol Sci ; 21(17)2020 Aug 27.
Article in English | MEDLINE | ID: covidwho-831264

ABSTRACT

Outside of Mycobacterium tuberculosis and Mycobacterium leprae, nontuberculous mycobacteria (NTM) are environmental mycobacteria (>190 species) and are classified as slow- or rapid-growing mycobacteria. Infections caused by NTM show an increased incidence in immunocompromised patients and patients with underlying structural lung disease. The true global prevalence of NTM infections remains unknown because many countries do not require mandatory reporting of the infection. This is coupled with a challenging diagnosis and identification of the species. Current therapies for treatment of NTM infections require multidrug regimens for a minimum of 18 months and are associated with serious adverse reactions, infection relapse, and high reinfection rates, necessitating discovery of novel antimycobacterial agents. Robust drug discovery processes have discovered inhibitors targeting mycobacterial membrane protein large 3 (MmpL3), a protein responsible for translocating mycolic acids from the inner membrane to periplasm in the biosynthesis of the mycobacterial cell membrane. This review focuses on promising new chemical scaffolds that inhibit MmpL3 function and represent interesting and promising putative drug candidates for the treatment of NTM infections. Additionally, agents (FS-1, SMARt-420, C10) that promote reversion of drug resistance are also reviewed.


Subject(s)
Anti-Bacterial Agents/pharmacology , Membrane Transport Proteins/metabolism , Mycobacterium Infections, Nontuberculous/drug therapy , Nontuberculous Mycobacteria/metabolism , Anti-Bacterial Agents/therapeutic use , Bacterial Proteins/metabolism , Biological Transport/drug effects , Drug Discovery , Drug Resistance, Multiple, Bacterial/drug effects , Gene Expression Regulation, Bacterial/drug effects , Humans , Iodophors/pharmacology , Iodophors/therapeutic use , Isoxazoles/pharmacology , Isoxazoles/therapeutic use , Mycobacterium Infections, Nontuberculous/metabolism , Mycolic Acids/metabolism , Nontuberculous Mycobacteria/drug effects , Polysaccharides/pharmacology , Polysaccharides/therapeutic use , Spiro Compounds/pharmacology , Spiro Compounds/therapeutic use
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