Exploring of N-phthalimide-linked 1,2,3-triazole analogues with promising ­anti-SARS-CoV-2 activity: synthesis, biological screening, and molecular modelling studies

Figures & data

Figure 1. Used drugs for the treatment of SARS-CoV-2 infection.

Figure 2. (A) docking pose of compound 11 in complex with M^pro (PBD ID 5R80) (left) and the 2D interaction map (right) showing the fundamental interactions of certain moieties in 11 with the protein; (B) The suggested modification aiming to improve its binding with the protein and enhance its anti-Covid activity.

Scheme 1. Synthesis of phthalimide Schiff base with terminal alkyne tether 4.

Scheme 2. Synthesis of 1,2,3-triazole-phthalimide hybrids with phenylacetamide tethers 6a-g.

Scheme 3. Synthesis of 1,2,3-triazole-phthalimide hybrids bearing aromatic ring 8a-h.

Scheme 4. Synthesis of 1,2,3-triazole-phthalimide hybrids bearing glycosyl moiety 10a-b.

Table 1. Antiviral activity of novel phthalimide-based triazole inhibitors by propagation in Vero E6 cells.

Comp.ID	Scaffold	SARS-CoV-2 antiviral activity (%)		(API)^a	CT/A^b	Vero E6 cytotoxicity (mM)
		1 mM	10 mM
6a	4-carboxyphenyl	87.82	94.96	0.98	9.95	7.6 ± 99.5
6b	2-iodophenyl	68.45	94.37	0.97	6.50	4.3 ± 65.0
6c	2-fluoro-4-iodophenyl	67.11	93.01	0.96	2.99	2.3 ± 29.9
6d	4-nitrophenyl	69.74	94.82	0.98	7.05	5.4 ± 70.5
6e	4-fluorophenyl	74.74	92.87	0.96	10.80	8.3 ± 108
6f	4-methylbenzyl	72.16	89.33	0.92	3.17	2.4 ± 31.7
6g	4-fluorobenzyl	82.15	94.29	0.97	9.75	7.4 ± 97.5
6h	4-chlorobenzyl	80.19	92.29	0.95	6.02	4.6 ± 60.2
		1 mM	10 mM
8a	4-fluorophenyl	79.35	93.70	0.96	12.7	9.7 ± 127.0
8b	4-carboxyphenyl	63.74	88.00	0.91	4.57	3.5 ± 45.7
8c	p-nitrophenyl	81.13	93.34	0.96	8.62	6.6 ± 86.2
8d	3-fluoro-4-methylphenyl	54.40	89.40	0.92	4.06	3.1 ± 40.5
8e	2-fluorophenyl	83.58	95.16	0.98	6.59	5.0 ± 65.9
8f	Ethyl benzoate	69.13	88.07	0.91	6.99	5.3 ± 69.9
8g	3,4-dichlorophenyl	75.77	93.44	0.96	2.84	2.2 ± 28.4
8h	4-acetylphenyl	77.71	93.79	0.96	4.28	3.3 ± 42.8
10a		80.74	89.10	0.92	6.46	4.9 ± 64.6
10b		67.78	87.82	0.90	10.80	8.2 ± 108.0
Remdesivir	NA	92.72	96.72	NA	4.31	3.3 ± 43.1

^aAntiviral potency index: It is the ratio of the inhibition % of the tested compounds to that of Remdesivir at 10 μM; 1 = Identical effect.

^bCytotoxicity/activity (10 mM) parameter.

Figure 3. Dose starting from 10 uM of the tested compounds.

Table 2. Inhibitory data of selected derivatives against SARS-CoV-2 M^pro.

Comp. ID	Chemical structure	IC50 (mM)
6a		112.8 ± 5.75
6 g		90.09 ± 4.59
10a		1088 ± 55.5
Lopinavir		148.8 ± 7.48

Figure 4. Docked poses of M^pro protease (PDB ID: 5R80) complexed with Z18197050 and 6 g compound with 2D interaction map for 6 g (right) and 3D interaction map of both aligned compounds (left).

Table 3. Calculation of certain properties of compounds 6f, 6i, and 10a in comparison with reported drugs as predicted by OSIRIS Property Explorer and Molinspiration tools.

ID	Molecular properties				Druggability		Toxicity risks				%ABS
	TPSA	Mwt	Solubility	clogP	Druglikeness	Drug-score	M	T	I	R
6a	156	524	−4.69	3.36	−6.57	0.28					55.18
6g	118	512	−4.81	3.74	−6.1	0.28					68.29
10a	204	677	−5.61	2.10	−6.32	0.18					38.62
GC-376	179	485	−2.75	−0.97	−28.75	0.37					47.24
Lopinavir	120	628	−6.13	4.85	7.64	0.17					67.60

https://www.organic-chemistry.org/prog/peo.

The calculation of %ABS was done using this equation ABS = 109−(0.345× TPSA). Green colour encodes no side effects will be reported.

Table 4. Molecular mechanics parameters and molecular orbital spatial distribution and localisation for the HOMO-LUMO of representative compounds, 6a, 6 g, and 10a.

Parameter	6a	6g	10a
Scaffold
Active fragments
Molecular orbitals
SCF energy (kcal/mol)	−253	−247	−345
Dipole (D)	8.53	4.58	7.98
Electrons	194	190	256
EHOMO (eV)	−1.3	−1.2	−1.4
ELUMO (eV)	−8.91	−8.85	−9.04
Delta (eV)	7.63	7.60	7.70

Data availability

The authors confirm that the data supporting the findings of this study are available within the article and/or its supplementary materials.