Table 1 Antithrombotic small molecule inhibitors targeting on VTIs

Rutin

10 μM

b’ domain and x-linker

Inhibits the aggregation of platelets and the formation of fibrin, and inhibits thrombosis at 0.5 mg/kg in vivo without causing prolonged bleeding time

PDI

[112]

Isoquercetin

2.5 μM

b’ domain

Used in anti-thrombotic clinical trials for cancer patients, it can effectively reduce the formation of thrombus (thrombin formation decreased by 51%) by taking 1000 mg orally every day

PDI

[113]

Myricetin

–-

a domain

Inhibit platelet activation, reduce the interaction between platelets and collagen, inhibit thrombosis, and do not affect the process of hemostasis

PDI, ERp5

[114]

Tannic acid

 < 1.68 nM

CXXC motif

Inhibits PDI activity, platelet activation, and thrombus formation

PDI

[115]

Bepristat 1a

0.7 μM

b’ domain

Inhibit platelet aggregation and thrombus formation in a laser-induced thrombosis model in mice at 15 mg/kg

PDI

[116]

Bepristat 2a

1.2 μM

b’ domain

Inhibit platelet aggregation and thrombus formation in a laser-induced thrombosis model in mice at 15 mg/kg

PDI

[116]

ML359

250 nM

b’ domain

Inhibit platelet aggregation and thrombosis, and has no cytotoxicity to HEK 293, HepG2, HeLa cell lines

PDI

[117, 118]

Juglone

1.61 ± 0.11 μM

a′ domain

Juglone (1—5 μM) concentration-dependently inhibited platelet aggregation caused by all three agonists with IC50 values of 1.46 ± 0.19 μM, 1.70 ± 0.14 μM, and 2.51 ± 0.19 μM, respectively

PDI

[119]

Rosmarinic acid

176.82 ± 11.7 μM

a’ domain

Inhibit platelet aggregation

ERp57

[120]

ADTM

100–300 μM

–-

Inhibit the expression of P-selectin and the activation of αIIbβ3, inhibit platelet aggregation and thrombosis in vivo

ERp57, ERp72, ERp5, PDI

[121]

Zafirlukast

5–10 μM

a and a′ domain

Platelet aggregation in response to collagen had an IC₅₀ value of 1.66 μM

PDI, ERp57, ERp72

[122, 123]

RB-11-ca

10 ± 1.1 μM

a and a′ domain

The effect of RB-11-ca on HeLa cell proliferation demonstrates that RB-11-ca shows micromolar inhibition (23.9 μM) of cell proliferation

PDI

[124, 125]

P1

1.7 ± 0.4 μM

a′ domain

P1 shows low-micromolar inhibition of cell proliferation against six cancer cells

PDI

[126]

Diethylstilbestrol

–-

–-

Diethylstilbestrol cause a more pronounced inhibition of receptor-mediated than of voltage-dependent Ca²⁺ channels

PDI

[127]

NOV-002

–-

–-

The mechanism of action of NOV-002 is the modulation of cellular redox balance

PDI

[128]

Piericones A

0.15 ± 0.04 μM

b′ and xa′ domain

Piericone A significantly inhibited platelet aggregation and fibrin formation in vitro and thrombus formation in vivo by inhibiting extracellular PDI without increasing the bleeding risk

PDI

[129]