An Update on Pharmacological Relevance and Chemical Synthesis of Natural Products and Derivatives with Anti SARS-CoV-2 Activity

Abstract

Natural products recognized traditionally as a vital source of active constituents in pharmacotherapy. The COVID-19 infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly transmissible, pathogenic, and considered an ongoing global health emergency. The emergence of COVID-19 globally and the lack of adequate treatment brought attention towards herbal medicines, and scientists across the globe instigated the search for novel drugs from medicinal plants and natural products to tackle this deadly virus. The natural products rich in scaffold diversity and structural complexity are an excellent source for antiviral drug discovery. Recently the investigation of several natural products and their synthetic derivatives resulted in the identification of promising anti SARS-CoV-2 agents. This review article will highlight the pharmacological relevance and chemical synthesis of the recently discovered natural product and their synthetic analogs as SARS-CoV-2 inhibitors. The summarized information will pave the path for the natural product-based drug discovery of safe and potent antiviral agents, particularly against SARS-CoV-2.

Keywords: COVID-19; SARS-CoV-2; anti-SARS-CoV-2 activity; biological activity; coronavirus; natural product derivatives; natural products.

Figure 1

Schematic representation of SARS‐CoV‐2 and its structural proteins.

Figure 2

Chemical structure of Baicalein (1) and Baicalin (2) isolated from Scutellaria baicalensis roots.

Figure 3

(A) SARS‐CoV‐2 3CL protease in complex with baicalein (1) (PDB 6 M2 N). (B) Interaction between Baicalein (1) and surrounding residues (SARS‐CoV‐2 3CL protease) (PDB 6 M2 N).

Scheme 1

Synthesis of Baicalein (1) from trimethoxy phenol (3) via chalcone (4).

Scheme 2

Synthesis of Baicalin (2) from Baicalein (1).

Figure 4

The chemical structure of Carolacton (14) produces by myxobacterium Sorangium cellulosum.

Scheme 3

Synthesis of carolacton (14) using S. Hallside et al. methodology.

Scheme 4

Synthesis of carolacton (14) using T. P. Kuilya et al. methodology.

Figure 5

Chemical structure of chloroquine (48) and hydroxychloroquine (49), analogs of antimalarial drug quinine (50) extracted from the bark of Cinchona tree.

Scheme 5

Synthesis of chloroquine (48) from 4,7‐dichloroquinoline (55) and 4‐diethylamino‐1‐methylbutylamine (59).

Scheme 6

Synthesis of hydroxychloroquine (49) from 4,7‐dichloroquinoline (55) with 2‐((4‐aminopentyl)(ethyl)amino)ethanol (65).

Figure 6

Chemical structure of emetine (66) isolated from the root of Carapichea ipecacuanha.

Scheme 7

Synthesis of emetine (66) from homoveratrylamine (67).

Figure 7

Chemical structure of glycyrrhizin (75) isolated from the roots of the plants′ Glycyrrhiza glabra and glycyrrhetinic acid (76).

Figure 8

Chemical structure of Homoharringtonine (77) isolated from the plant Cephalotoxus fortun

Scheme 8

Synthesis of Homoharringtonin (77) using X Ju et al. methodology.

Figure 9

Chemical structure of ivermectin (88), a derivative of natural product avermectin isolated from the bacterium Streptomyces avermitilis.

Scheme 9

Synthesis of Ivermectin [B1a (91) & B1b (92)] by catalytic hydrogenation of the cis‐22,23‐ double bond of the avermectin [B1a (89) & B1b (90)].

Figure 10

Chemical structure of resveratrol (93).

Scheme 10

Synthesis of Resveratrol (93) from 3,5‐dimethoxy‐1‐ethynyl‐benzene (94) and 4‐iodoanisole (95).

Figure 11

Chemical structure of Remdesivir (99) synthesized by structural modification of tubercidin (100) isolated from Streptomyces tubercidicus. The CN group in 99 was inspired by natural cyanide toyocamycin (101) isolated from Streptomyces toyocmnsis.

Figure 12

(A): The nsp12‐nsp7‐nsp8 complex bound to the template‐primer RNA and triphosphate form of Remdesivir (RTP) (PDB 7BV2). (B) Interaction between Remdesivir triphosphate and surrounding residues (RNA dependent RNA polymerase (PDB 7BV2)^[209] (C): SARS‐CoV‐2 RdRp in complex with 4 Remdesivir monophosphates (PDB 7 L1F).

Scheme 11

Synthesis of Remdesivir (99) by coupling blocks 103 and 108 in gram scale using Wang et al. methodology.

Figure 13

Chemical structure of EIDD‐1931 (113) and EIDD‐2801 (115) derived from natural product uridine (114).

Scheme 12

Synthesis of EIDD‐2801 (115) in gram scale from uridine 114 using the patented methodology.

Scheme 13

Synthesis of EIDD‐2801 (115) from uridine 114 using A Steiner et al. methodology.