Design and synthesis of novel [60]fullerene derivatives as potential HIV aspartic protease inhibitors

[structure] Two water-soluble fullerene derivatives have been computer-designed and synthesized. They may exhibit interesting anti-HIV activity owing to the presence of two ammonium groups strategically located on the spheroid surface.     

Microwave assisted organic synthesis (MAOS) of small molecules as potential HIV-1 integrase inhibitors

Integrase (IN) represents a clinically validated target for the development of antivirals against human immunodeficiency virus (HIV). In recent years our research group has been engaged in the stucture-function study of this enzyme and in the development of some three-dimensional pharmacophore models which have led to the identification of a large series of potent HIV-1 integrase strand-transfer inhibitors (INSTIs) bearing an indole core. To gain a better understanding of the structure-activity relationships (SARs), herein we report the design and microwave-assisted synthesis of a novel series of 1-H-benzylindole derivatives.     

Syntheses of conformationally constricted molecules as potential NAALADase/PSMA inhibitors

Two six-membered ring targeted analogues of PSMA inhibitors (4a and 4b) were designed on the basis of a computational analysis and synthesized. (E,Z)-Diene 10 was subjected to the nitroso Diels-Alder reaction to give the 1,4-trans six-membered ring adduct, 4a. The cis isomer 4b was derived from similar nitroso cycloaddition reactions with the corresponding (E,E)-diene and separately from cyclohexadiene. The IC(50) values of 4a and 4b in a NAALADase assay were found to be 0.9 and 0.1 microM, respectively. [reaction: see text]     

Asymmetric synthesis of hydroxy-skipped bishomo-inositols as potential glycosidase inhibitors

Four isomeric hydroxy-skipped bishomo-inositol analogs have been synthesized from both enantiomers of 5-hydroxymethyl-2-cyclohexenone. Sharpless asymmetric dihydroxylation and substrate-directed anionic hydroxymethylation are the key reactions which have been employed successfully for the synthesis of new cyclitols. The synthesized cyclitols have been screened for their inhibitory effect on α- and β-glycosidases.     

Virtual screening of approved drugs as potential SARS-CoV-2 main protease inhibitors

The global emergency caused by COVID-19 makes the discovery of drugs capable of inhibiting SARS-CoV-2 a priority, to reduce the mortality and morbidity of this disease. Repurposing approved drugs can provide therapeutic alternatives that promise rapid and ample coverage because they have a documented safety record, as well as infrastructure for large-scale production. The main protease of SARS-CoV-2 (Mpro) is an excellent therapeutic target because it is critical for viral replication; however, Mpro has a highly flexible active site that must be considered when performing computer-assisted drug discovery. In this work, potential inhibitors of the main protease (Mpro) of SARS-Cov-2 were identified through a docking-assisted virtual screening procedure. A total of 4384 drugs, all approved for human use, were screened against three conformers of Mpro. The ligands were further studied through molecular dynamics simulations and binding free energy analysis. A total of nine currently approved molecules are proposed as potential inhibitors of SARS-CoV-2. These molecules can be further tested to speed the development of therapeutics against COVID-19.     

Efficient synthesis of an enantiopure beta-lactam as an advanced precursor of thrombin and tryptase inhibitors

A new and efficient synthesis of a beta-lactam that is an advanced precursor of inhibitors of thrombin and tryptase is reported. The reaction sequence is based on the use of an inexpensive enantiomerically pure starting material and is designed to allow access to both enantiomers of the target molecules by epimerization of a side-product obtained along the synthesis. An improved procedure for the epimerization step that takes advantage of the use of a polymer-supported and recyclable phase-transfer catalyst is described.     

The synthesis of 7-deazaguanines as potential inhibitors of guanosine triphosphate cyclohydrolase I

Variously substituted 7-deazaguanines are of interest as inhibitors of GTP cyclohydrolase I, the first enzyme in the biosynthetic pathway leading to dihydrofolate and tetrahydrobiopterin. Methods are described for the synthesis of 7-deazaguanines substituted at positions 2, 6 and 9 (purine numbering) such that a wide diversity of compounds can be prepared. These methods supplement our previous work that established routes for the synthesis of 7- and 8-substituted 7-deazaguanines. Emphasis is placed on the properties of 2-thioalkyl pyrimidines as intermediates because they provide the basis for a traceless solid-state synthesis of purines, pteridines, and their analogues. Compounds prepared have been assessed in a primary screen for their ability to inhibit GTPCH I and 8-methyldeazaguanine has been shown to be significantly more potent than any inhibitor yet described. Several compounds appeared to undergo transformation by GTPCH I; with the aid of a model reaction, their behaviour can be interpreted in the context of the mechanism of the hydrolytic phase of GTPCH I.     

A general strategy for the synthesis of azapeptidomimetic lactams

A selection of azapeptidomimetics containing constraining lactam rings have been prepared by Mitsunobu cyclization of serine/homologated serine-azaalanine derivatives. These include sterically-congested β-lactams, as well as γ-butyrolactam and δ-valerolactam analogs. A novel azaamino acid acylation method was developed to prepare the sterically demanding α-benzyl-serine-azaalanine precursor. In all cases, the Mitsunobu conditions were highly efficient in forming the desired azapeptidomimetic lactams. The reported process represents a general strategy for the synthesis of peptidomimetic structures with a constraining lactam ring.     

SmI2 reduced thioesters as synthons of unstable acyl radicals: direct synthesis of potential protease inhibitors via intermolecular radical addition

Aromatic alpha-heterosubstituted thioesters were found to undergo radical 1,4-addition reactions to a series of alpha,beta-unsaturated amides and one ester when subjected to the single electron reducing agent, samarium diiodide, at -78 degrees C. These thioesters derived from alpha-amino acids represent a synthetically useful synthon of unstable acyl radicals. This reaction conveniently provides access to gamma-ketoamides and esters in yields up to 90%, structures that are common in various protease inhibitors derived from peptides. Examples with acryloyl and methacryloyl derivatives of alpha-amino acids and dipeptides lead directly to tri- and tetrapeptide mimetics possessing the gamma-ketoamide functionality. No epimerization was observed with the mild conditions used for these reactions.     

Novel branched isocyanides as useful building blocks in the Passerini-amine deprotection-acyl migration (PADAM) synthesis of potential HIV-1 protease inhibitors

Novel branched isocyanides have been prepared from l-serine and used as building blocks in the Passerini-amine deprotection-acyl migration (PADAM) sequence for the preparation of compounds with activity against HIV-1 protease.     

Stereoselective synthesis of beta-substituted phenylalanine-beta-phenylisoserine-derived tripeptides using N-cinnamoyl-L-proline as template: synthesis of structural analogues of HIV protease inhibitors

N-Cinnamoyl-L-proline can be used as a template on which beta-substituted phenylalanine and beta-phenylisoserine residues can be synthesized leading to tripeptide derivatives as structural analogues of HIV protease inhibitors.     

Small molecules as inhibitors of cyclin-dependent kinases

Cell division (mitosis) is one of the basic requirements for multicellular oranisms. The capability of a cell to replicate enables a complex assembly to be created. Faulty regulation of the control mechanism in the cell cycle leads to an excessive cell proliferation and is the cause of cancer. The key position of the cyclin-dependent kinases (CDKs) and their direct partners, as well as the fact that the majority of malign illnesses show defects in at least one of these key players of the cell cycle, is of great interest for the development of low-molecular-weight CDK inhibitors. In this Review an overview of the different structural classes of ATP-competitive inhibitors of CDKs are given, whose devlopment was aimed at battling cancer. The Review shows how far the development of selective CDK inhibitors has progressed and to what extent the expectations for such drugs have so far been fulfilled.     

Facile synthesis of 9-substituted 9-deazapurines as potential purine nucleoside phosphorylase inhibitors

A facile synthesis of 9-substituted 9-deazapurines as potential inhibitors of purine nucleoside phosphorylase has been achieved by the direct Friedel-Crafts aroylation or arylmethylation of 9-deazapurines using trifluoromethanesulfonic acid as catalyst. The aroylated 9-deazapurines could be transformed into the corresponding 9-aryimethyl derivatives by the Wolff-Kishner reaction. A novel synthesis of 9-deazahypoxanthine was also developed by treatment of 4-hydroxy-5-phenylazo-6-methylpyrimidin-2-thione with triethyl orthoformate in trifluoroacetic acid (TFA) to yield 8-oxo-7H-2-phenylpyrimido[5,4-c]pyridazin-6-thione followed by Raney nickel reduction.     

Aspartic protease inhibitors: expedient synthesis of 2-substituted statines

[reaction: see text]. General stereocontrolled synthesis of all four (2,3)-stereoisomers of 2-substituted statines is described. The 2,3-syn and 2,3-anti isomers were synthesized via beta-ketoester reduction and aldol reactions, respectively. Peptides containing 2-substituted statines inhibit porcine pepsin with nanomolar IC50 values.     

New approaches to the industrial synthesis of HIV protease inhibitors

Efficient and industrially applicable synthetic processes for precursors of HIV protease inhibitors (Amprenavir, Fosamprenavir) are described. These involve a novel and economical method for the preparation of a key intermediate, (3S)-hydroxytetrahydrofuran, from l-malic acid. Three new approaches to the assembly of Amprenavir are also discussed. Of these, a synthetic route in which an (S)-tetrahydrofuranyloxy carbonyl is attached to l-phenylalanine appears to be the most promising manufacturing process, in that it offers satisfactory stereoselectivity in fewer steps.     

Design and synthesis of new C-nucleosides as potential adenosine deaminase inhibitors

A number of new pyrazolo[3,4-c] and [4,3-b]pyridine C-nucleosides, which can be viewed as 4- or 6-deazaformycin analogues were synthesized and examined as potential adenosine deaminase (ADA) inhibitors. The compounds were prepared through the condensation of a suitably substituted, lithiated 2- or 4-methylpyridine with tri-O-benzyl-d-ribonolactone, followed by borohydride reduction of the resulting hemiacetals, intramolecular Mitsunobu cyclisation of the derived diols, formation of the pyrazolopyridine ring system and subsequent removal of the protecting groups. These derivatives were designed on the structural basis provided by docking simulations performed within the enzyme catalytic site, however they demonstrated weak ADA inhibitory activity. Theoretical calculations assisted in the interpretation of the obtained biological data, thus providing guidance for rational structural modifications within this molecular scaffold.     

Design and synthesis of cinanserin analogs as severe acute respiratory syndrome coronavirus 3CL protease inhibitors

The severe acute respiratory syndrome (SARS) coronavirus 3CL protease is an attractive target for the development of anti-SARS drugs. In this paper, cinanserin (1) analogs were synthesized and tested for the inhibitory activities against SARS-coronavirus (CoV) 3CL protease by fluorescence resonance energy transfer (FRET) assay. Four analogs show significant activities, especially compound 26 with an IC(50) of 1.06 microM.     

Synthesis of macrocyclic,potential protease inhibitors using a generic scaffold

A generic macrocyclic peptide structure 2 was designed as a potential inhibitor of a range of proteinases, by using as a basis for the design the known structures of a series of enzyme-inhibitor complexes. The macrocyclic nature of the target 2 was chosen so as to reduce the entropic advantage in the hydrolytic enzymatic step, and thereby to inhibit the function of the enzyme. The nature of the linking group was identified as a benzoxazole by molecular modeling, so as to preserve the recognized conformation of the peptide chain. The specificity of the potential inhibitor was tuned by variation of the P(1) group (by incorporating phenylalanine, aspartic acid, or lysine), to allow recognition by different enzyme classes. The targets were prepared from the bis-amino acid derivative 5, itself prepared using the Pd-catalyzed coupling of an organozinc reagent with the iodobenzothiazole 7 and subsequent macrocyclization of the open-chain derivatives 22-24 using HATU. None of the macrocylic compounds 25, 28-30, and 32 inhibited their target enzymes. NMR and MS studies on the interaction of macrocycle 29 and chymotrypsin established that compound 29 was in fact a substrate of the enzyme. This result indicated that while the design had been partially successful in identifying a compound that bound, the reduction in entropic advantage due to its macrocyclic nature was not sufficient to allow 29 to act as an inhibitor.