Abstract

The heterocyclic compounds have great importance in medicinal chemistry. One of the most important heterocycles in medicinal chemistry are thiophenes possessing wide spectrum of biological properties like anti-cancer, anti-inflammatory, anti-bacterial, anti-fungal, anti-tumor, anti-malarial, anti-microbial, anti-anxiety and many more activities. This skeleton is an important pharmacophore considered as a privileged structure. This review highlights the recent advances in the synthesis of thiophene derivatives with wide variety of pharmacological activities.

Keywords

Heterocycle, Thiophene, Antimicrobial, Pharmacological activities

Introduction

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Some Of The Therapeutic Activities Of Thiophene

Anti Inflammatory Activity:

The mechanism of action of anti-inflammatory drugs containing thiophene is to inhibit the activity of cyclooxygenase (COX) and lipoxygenase (LOX) enzymes:

• Cyclooxygenase (COX): An enzyme that the body uses to produce prostaglandins, which are involved in inflammatory events like increased blood flow and vascular permeability.
• Lipoxygenase (LOX): An enzyme that produces leukotrienes, which promote allergic inflammation ^[19]

Example: Tenidap

       
           
       
Figure-2: Anti-inflammatory Activities

Anti-Cancer Activity:

Anti-cancer drugs containing thiophene can work by binding to cancer-specific proteins, inhibiting signalling pathways, or disrupting microtubules:

• Binding to cancer-specific proteins

Thiophene analogues can bind to oncogenic kinases like FLT3 tyrosine kinase, checkpoint kinase, PI3K, IKK-2.

• Inhibiting signalling pathways

Thiophene analogues can inhibit signalling pathways involved in cancer.

• Disrupting microtubules

Some thiophene-containing drugs, like ELR510444, can disrupt microtubules to inhibit cell proliferation.

• Suppressing mitosis

Nocodazole, a thiophene-containing drug, can suppress mitosis by binding to ?-tubulin.

• Inhibiting tubulin polymerization

Benzothiophene derivatives can inhibit tubulin polymerization by binding to the colchicine binding site ^[20]. 

Example: Raltitrexed

       
           
       
Figure-3: Anti-cancer activity

ANTI TUMOUR ACTIVITY:

Thiophene-based anti-tumour drugs work in a variety of ways, including:

• Binding to protein targets: Thiophene analogues can bind to cancer-specific proteins. 
• Inhibiting signalling pathways: Thiophene analogues can inhibit signalling pathways involved in cancer. 
• Targeting oncogenic kinases: Some thiophene-based drugs target oncogenic kinases like FLT3 tyrosine kinase, PI3K, and IKK-2. 
• Suppressing mitosis: Some thiophene-based drugs, like Nocodazole, bind to ?-tubulin to suppress mitosis.
• Disrupting microtubules: Some thiophene-based drugs, like ELR510444, disrupt microtubules to inhibit cell proliferation.
• Inhibiting tubulin polymerization: Some thiophene-based drugs, like Benzothiophene derivatives, bind to the colchicine binding site to inhibit tubulin polymerization.
• Inhibiting ribonucleotide reductase: Some thiophene-based drugs, like triapine, inhibit the enzyme ribonucleotide reductase [21].

Example: Thiophen Furin

       
           
       
Figure-4: Anti tumour activity

Local Anesthetic Activity

The mechanism of action of local anaesthetic drugs containing thiophene, like articaine, is to block nerve conduction by binding to sodium channels in the nerve: 

• Binding

Articaine binds to the voltage-gated sodium channels in the nerve, reducing the amount of sodium that can enter the cell. This prevents the threshold potential from being reached, stopping the conduction of impulses. 

• Lipid solubility

Articaine's thiophene ring makes it more lipid soluble, which helps it diffuse across the nerve membrane to reach its target receptors. 

Ester group

Articaine also contains an ester group, which causes it to be metabolized and excreted in the kidneys after hydrolysis in the plasma ^[22].

Example: Articaine

       
           
       
Figure-5: Local anaesthetic Activity

Anti Tubercular Activity:

Anti-tubercular drugs containing thiophene may have a few different mechanisms of action, including:

• Inhibiting Pks13

Some thiophene compounds kill Mycobacterium tuberculosis (Mtb) by inhibiting Pks13, which is required for mycolic acid biosynthesis. This mechanism of action is bactericidal and similar to the first-line drug isoniazid. 

• Allosterically targeting DNA gyrase

Some thiophene-based compounds bind to a pocket on DNA gyrase that is remote from Domain A. This binding site is potentially druggable and may reduce the likelihood of cross-resistance to fluoroquinolones. 

• Inhibiting DprE1

Some thiophene compounds may inhibit DprE1 to exert antimycobacterial activity ^[23].

Example: TCA1

       
           
       
Figure-6: Anti tubercular activity

Anti-Malarial Activity:

The mechanism of action of anti-malarial drugs containing thiophene is

• Inhibition of lipid synthesis: MMV-0206 disrupts parasite membrane function.
• Inhibition of pyrimidine synthesis: DSM-1 inhibits pDHODH, disrupting DNA synthesis.
• Mitochondrial electron transport inhibition: Thiostrepton disrupts energy production.
• Cysteine protease inhibition: K77 disrupts haemoglobin degradation.
• Phospholipid synthesis inhibition: SJ000030570 disrupts membrane function.

Anti-malarial Drugs

1. MMV-0206: Inhibits plasmodial lipid synthesis, disrupting parasite membrane function.

2. DSM-1: Inhibits plasmodial dihydroorotate dehydrogenase (pDHODH), disrupting pyrimidine synthesis.

3. Thiostrepton: Inhibits plasmodial mitochondrial electron transport, disrupting energy production.

4. K77: Inhibits plasmodial cysteine proteases, disrupting haemoglobin degradation.

5. SJ000030570: Inhibits plasmodial phospholipid synthesis, disrupting membrane function ^[24].

Example: Benzothiophene

       
           
       
Figure-7: Anti-malarial  activity

ANTI PSYCHOTIC ACTIVITY:

The mechanism of anti-psychotic drugs containing thiophene shows mechanism such as inhibiting the enzymes cyclooxygenase (COX) and lipoxygenase (LOX). 

• Thiothixene: Blocks dopamine, serotonin, histamine, alpha1/alpha2, and muscarinic receptors
• First-generation antipsychotics: Blocks dopamine, serotonin, histamine, alpha1/alpha2, and muscarinic receptors
• Second-generation antipsychotics: Blocks D2 dopamine receptors and acts as a serotonin receptor antagonist
• Atypical antipsychotics: Enhances 5-HT, norepinephrine, and/or dopamine transmission ^[25].

Example: Olanzapine

       
           
       
Figure-8: Anti-psychotic activity

CONCLUSION

In this review I have described the recent advances in pharmacological diversification of thiophene derivatives. Some of the pharmacological activities that has described in this review are anti-cancer, anti-malarial, anti-inflammatory, anti-psychotic, local anesthetic, anti-tumor and anti-tubercular activities.

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