Reviews on Biological Activity, Clinical Trial and Synthesis Progress of Small Molecules for the Treatment of COVID-19

Abstract

COVID-19 has broken out rapidly in nearly all countries worldwide, and has blossomed into a pandemic. Since the beginning of the spread of COVID-19, many scientists have been cooperating to study a vast array of old drugs and new clinical trial drugs to discover potent drugs with anti-COVID-19 activity, including antiviral drugs, antimalarial drugs, immunosuppressants, Chinese medicines, M^pro inhibitors, JAK inhibitors, etc. The most commonly used drugs are antiviral compounds, antimalarial drugs and JAK inhibitors. In this review, we summarize mainly the antimalarial drugs chloroquine and hydroxychloroquine, the antiviral drugs Favipiravir and Remdesivir, and JAK inhibitor Ruxolitinib, discussing their biological activities, clinical trials and synthesis progress.

Keywords: COVID-19; Chloroquine; Favipiravir; Hydroxychloroquine; Remdesivir; Ruxolitinib.

Fig. 1

Structure of chloroquine (CLQ) and hydroxychloroquine (CLQ-OH)

Fig. 2

Structure of hepatitis C virus (HCV) antiviral agents against COVID-19

Fig. 2

Structure of hepatitis C virus (HCV) antiviral agents against COVID-19

Fig. 3

Structure of hepatitis B virus (HBV) antiviral agents against COVID-19

Fig. 4

Structure of human immunodeficiency virus (HIV) antiviral agents against COVID-19

Fig. 5

Structure of Influenza antiviral agents against COVID-19

Fig. 6

Structure of Ebola antiviral agents against COVID-19

Fig. 7

Structure of other antiviral agents against COVID-19

Fig. 8

Structure of GS-441524 (remdesivir)

Fig. 9

Compounds exhibiting good effectiveness in COVID-19 cell lines

Fig. 9

Compounds exhibiting good effectiveness in COVID-19 cell lines

Fig. 10

Structure and biological activity of Carmofur, Baicalein, 11a, 11b, 11r and N₃

Fig. 11

Structure of GENZ123346

Fig. 12

Structure of four Janus kinase (JAK) inhibitors

Fig. 13

Schematic representation of a coronavirus virion. Image reproduced from Ref. [59] with permission from Elsevier

Fig. 14

Comparison of severe acute respiratory syndrome coronavirus (SARS-CoV)-2 receptor binding domain (RBD)/human angiotensin-converting enzyme 2 (hACE2) complex structures (a) and the constructed SARS-CoV-2 RBD/hACE2 peptide complex (b). Image reproduced from Ref. [60] with permission from bioRxiv

Fig. 15

Structure of S-Protein/ACE2 complex. Image reproduced from Ref. [62] with permission from ACS

Fig. 16

Proposed mechanism of action for CLQ. CQ CLQ, RdRp RNA dependent RNA polymerase. Image reproduced from Ref. [74] with permission from Elsevier

Scheme 1

First generation synthesis of Chloroquine (CLQ)

Scheme 2

Compound II should be added an C-Cl at meta position

Scheme 3

Third generation synthesis of CLQ

Fig. 17

Molecular model of CLQ-OH interaction with sialic acids. Image reproduced from Ref. [74] with permission from Elsevier

Fig. 18

Molecular modeling simulations of CLQ and CLQ-OH binding to ganglioside. Image reproduced from Ref. [74] with permission from Elsevier

Fig. 19

Potential mechanisms of SARS-COV-2-induced injury of multiple organs and pharmacological effects of CLQ-OH on COVID-19. Blue arrows indicate the actions of SARS-COV-2. ACE2 is key for SARS-COV-2 entering cells in human organs. Red dashed lines indicate the potential mechanisms of the therapeutic and toxic effects of CLQ-OH on SARS-COV-2 and organs in COVID-19 patients. Image reproduced from Ref. [87] with permission from Elsevier

Scheme 4

Method for preparation of Hydroxychloroquine (CLQ-OH) by Alexander et al. [98]

Scheme 5

Method for preparation of CLQ-OH by Ashok et al. [99]

Scheme 6

Method for preparation of CLQ-OH by Min et al. [100]

Scheme 7

Preparation of CLQ-OH with a continuous-flow method

Scheme 8

Synthesis of Favipiravir by Takamatsu and Yonezawa [118]

Scheme 9

Preparation of Favipiravir by Hara et al. [119]

Scheme 10

Preparation of Favipiravir by Liu et al. [120]

Scheme 11

Preparation of Favipiravir by Li et al. [121]

Fig. 20

Structure of Remdesivir

Fig. 21

Structure and activity of (1) EC₅₀ = 1.98 μM; CC50 = 85 μM (Huh-7); C50 = 0.31 μM

Fig. 22

Structure and activity of GS-6620

Fig. 23

The complex structure of Remdesivir and SARS-CoV-2 RNA bound to RdRp complex. Image reproduced from Ref. [135] with permission from Wiley-VCH

Scheme 12

First generation synthesis of Rendesivir

Scheme 13

Second generation synthesis of Remdesivir

Scheme 14

Large-scale cyanation process using continuous flow chemistry synthesis of Remdesivir key intermediate

Scheme 15

Improved methodology for the synthesis of Remdesivir key intermediate by Xue et al. [157]

Scheme 16

Catalytic asymmetric synthesis of a key step of Remdisivir by Wang et al. [158]

Fig. 24

Ruxolitinib (1) docked into JAK2. Image reproduced from Ref. [160] with permission from Elsevier

Scheme 17

Preparation of racemic Ruxolitinib by Rodgers et al. [168]

Scheme 18

Gram-scale synthesis of (R)-Ruxolitinib by Haydl et al. [169]

Scheme 19

Preparation of Ruxolitinib and its phosphate by Deepshikha et al. [170]

Scheme 20

Preparation of Ruxolitinib by Zhang et al. [171] synthetic route one

Scheme 21

Preparation of Ruxolitinib by Zhang et al. [171] synthetic route 2