Drug repurposing for the treatment of COVID-19: Pharmacological aspects and synthetic approaches

Abstract

In December 2019, a new variant of SARS-CoV emerged, the so-called acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus causes the new coronavirus disease (COVID-19) and has been plaguing the world owing to its unprecedented spread efficiency, which has resulted in a huge death toll. In this sense, the repositioning of approved drugs is the fastest way to an effective response to a pandemic outbreak of this scale. Considering these facts, in this review we provide a comprehensive and critical discussion on the chemical aspects surrounding the drugs currently being studied as candidates for COVID-19 therapy. We intend to provide the general chemical community with an overview on the synthetic/biosynthetic pathways related to such molecules, as well as their mechanisms of action against the evaluated viruses and some insights on the pharmacological interactions involved in each case. Overall, the review aims to present the chemical aspects of the main bioactive molecules being considered to be repositioned for effective treatment of COVID-19 in all phases, from the mildest to the most severe.

Keywords: Coronavirus; Organic synthesis; SARS-CoV-2; Small molecules; Therapy.

Graphical abstract

Fig. 1

Structure of protease inhibitors used in the treatment of HIV infections.

Fig. 2

2D representation of the interactions of (a) LPV and (b) ATV in the M^pro active site , .

Scheme 1

Synthetic route of lopinavir.

Scheme 2

Synthetic route towards ritonavir.

Scheme 3

Synthetic route towards of atazanavir. NMM = N-Methylmorpholine.

Fig. 3

Structure of remdesivir and its active metabolite.

Scheme 4

Synthetic route towards remdesivir.

Fig. 4

Structure of TDF, tenofovir and their active metabolite.

Scheme 5

Synthetic route towards TDF. NMP = N-Methyl-2-pyrrolidone.

Fig. 5

Chemical structure of sofosbuvir and its active metabolite.

Fig. 6

Structural superposition of the HCV NS5B and SARS-CoV-2 polymerases. HCV NS5B is depicted in blue, SARS-CoV-2 nsp12 in yellow, sofosbuvir in orange . (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Scheme 6

Synthetic route towards sofosbuvir. TIPDSCl₂ = 1,3-Dichloro-1,1,3,3-tetraisopropyldisiloxane, DAST = Diethylaminosulfur trifluoride, NMI = N-Methylimidazole.

Fig. 7

Chemical structure of favipiravir and its active metabolite.

Scheme 7

Synthesis of favipiravir from methyl 3-amino-6-bromopyrazine-2-carboxylate.

Scheme 8

Synthesis of favipiravir starting from 2-aminopyrazine. TSA = N-chloro-N-methoxy-4-methylbenzenesulfonamide.

Fig. 8

Umifenovir (in orange) binding region in SARS-CoV-2 spike glycoprotein. Reprinted from International Journal of Antimicrobial Agents, 56, N. Vankadari, “Arbidol: A potential antiviral drug for the treatment of SARS-CoV-2 by blocking trimerization of the spike glycoprotein”, Page 2, with permission of Elsevier. Copyright 2020. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Scheme 9

Synthetic route towards umifenovir.

Fig. 9

Chemical structure chloroquine, hydroxichloroquine and amodiaquine.

Fig. 10

(a) Mills projection of the 9-O-acetyl-sialic acid subtype. (b) Simplified representation of the interactions between CQ/HCQ e o 9-O-Ac-SIA.

Scheme 10

Seminal synthetic approach towards chloroquine.

Scheme 11

One-pot procedure for the synthesis of amodiaquine.

Scheme 12

Flow process for the synthesis of hydroxychloroquine.

Fig. 11

Quinine and mefloquine structural representations.

Scheme 13

Classical method for the synthesis of mefloquine. PPA = polyphosphoric acid.

Scheme 14

Alternative method for the synthesis of intermediate 86.

Scheme 15

NTZ structure and its main metabolites.

Scheme 16

Synthetic route towards nitazoxanide.

Fig. 12

Structures of some ivermectins.

Scheme 17

Retrosynthetic design for ivermectin B1a.

Scheme 18

Synthetic route towards ivermectin B1a subunit A. TBDPSCl = t-butyldiphenylchlorosilane, NAPBr = 2-naphthylmethyl bromide, DMP = Dess-Martin periodinane, PPTS = pyridinium p-toluenesulfonate.

Scheme 19

Synthetic route towards ivermectin B1a subunit B. PPTS = pyridinium p-toluenesulfonate. DMP = Dess-Martin Periodinane, NMO = N-methylmorpholine N-oxide.

Scheme 20

Final step in the total synthesis of avermectin B1a. HMPA = Hexamethylphosphoramide, TBAF = tetra-n-butylammonium fluoride, DTBMP = 2,6-di-tert-butyl-4-methylpyridine.

Fig. 13

2D Representation of the interaction plots within the active site of SARS-CoV-2 M^Pro.

Scheme 21

Synthetic route towards emetine.

Fig. 14

Structure of gemcitabine and its active phosphorylated metabolite.

Scheme 22

Synthetic route towards chemotherapic drug gemcitabine. TBDMSOTf = tert-butyldimethylsilyl trifluoromethanesulfonate.

Fig. 15

Chemical structure of FDA-approved tyrosine kinase inhibitors.

Scheme 23

Synthetic route towards the tyrosine kinase inhibitor imatinib.

Scheme 24

Synthetic route towards the tyrosine kinase inhibitor dasatinib.

Fig. 16

Structure of the prodrug tamoxifen and its main active metabolites, afimoxifene and endoxifen.

Scheme 25

Synthetic approaches towards tamoxifen, an estrogen inhibitor.

Scheme 26

Seminal synthetic approach towards toremifene.

Scheme 27

Alternative synthetic route towards toremifene.

Fig. 17

First non-peptide AT1 antagonists, including losartan and its active metabolite.

Fig. 18

Model representation of losartan interaction with the AT₁ receptor.

Scheme 28

Synthetic approach towards losartan.

Fig. 19

Different representations for the structure of cycloporin A. (a) Angular chemical representation. (b) Amino acid residues sequence associated with the drug's pharmacodynamic interaction. (c) Peptide primary structure representation. d) Linear representation highlighting the intramolecular hydrogen bonds. MeBmt = (4R)-4-((E)-2-butenyl)-4-methyl-L-threonine residue; Abu = α-aminobutyric acid residue; Sar = sarcosine residue; MeLeu = N-methylleucine residue; MeVal = N-methylvaline residue; Ala = alanine residue; Val = valine residue; - - - - = Hydrogen bonds.

Scheme 29

Partial retrosynthetic rationalization toward cyclosporin A total synthesis.

Scheme 30

Synthetic route towards tetrapeptide fragment 186. AIBN = azobisisobutyronitrile, DETBT = 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one.

Scheme 31

Synthetic strategy towards the hexapeptide fragment 187. HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate.

Scheme 32

Final step in the total synthesis of cyclosporin A.

Fig. 20

Structure of promethazine, fluphenazine and chlorpromazine.

Fig. 21

CPZ/phospholipid monolayer interactions suggested by molecular dynamics simulation studies.

Scheme 33

Early protocol for the synthesis of promethazine as a mixture of enantiomers.

Scheme 34

Chemoenzymatic synthesis of enantioenriched enantiomers of promethazine.

Scheme 35

Synthetic approach towards chlorpromazine.

Scheme 36

Synthetic approach towards fluphenazine.

Scheme 37

Synthetic approach towards disulfiram.

Fig. 22

Binding models of DSF into SARS-CoV-2 main protease, 3CL^pro. (a) Depiction of the overall structure showing the Cys145 and His41 catalytic residues located in the active site cavity and (b) SARS-CoV-2 3CL^pro-DSF. . Reprinted from Journal of Biomolecular Structure and Dynamics, N. Lobo-Galo, M. Terrazas-López, A. Martínez-Martínez, Á.G. Díaz-Sánchez. “FDA-approved thiol-reacting drugs that potentially bind into the SARS-CoV-2 main protease, essential for viral replication” with permission of Taylor & Francis Ltd. Copyright 2020.

Scheme 38

Possible mechanism of reaction between DSF and 3CL^pro, SARS-CoV-2́s main protease.

Scheme 39

Synthetic route towards terconazole.

Fig. 23

Chemical structure of the teicoplanin complex.

Scheme 40

Synthesis of the precursor residues 245, 248 and 250 of the teicoplanin aglycone. Teoc-OBt = 1-[2-(trimethylsilyl)ethoxycarbonyloxy]benzotriazole. MEMCl = 2-methoxyethoxymethyl chloride.

Scheme 41

Synthesis of EFG tripeptide precursor 255 of teicoplanin aglycone. EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

Scheme 42

Synthesis of the ABCD ring system (part A) of teicoplanin aglycone. EDC = 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide, HOBt = hydroxybenzotriazole, TBAF = tetra-n-butylammonium fluoride.

Scheme 43

Synthesis of the ABCD ring system (part B) of teicoplanin aglycone. EDC = 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide, HOBt = hydroxybenzotriazole.

Scheme 44

Synthesis of the key intermediate 283 of teicoplanin aglycone. DEPBT = 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one.

Scheme 45

Final step in the teicoplanin aglycone synthesis.

Fig. 24

(a) Superposition of SARS-CoV-2 RBD, B38 and RBD-hACE2 [Protein Data Bank (PDB) ID 6LZG]. The B38 heavy chain is colored in cyan, the light chain in green, SARS-CoV RBD in magenta and hACE2 in light pink. [Protein Data Bank (PDB) ID 6LZG]. (b) The residues on RBD involved in both B38 and hACE2 binding (labeled in red) and involved in hACE2-RBD binding (highlighted in light pink) . Reprinted with permission from AAAS. Copyright 2020. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)