Development in medicinal chemistry via oxadiazole derivatives: patent spotlight 2020–2024

ABSTRACT

The oxadiazole derivatives are part of the azole family and have drawn significant interest in medicinal chemistry due to their wide range of biological activities and promising pharmacological profiles. This patent spotlight highlights the developments of the oxadiazole-based compounds reported between 2020 and 2024, with applications in treating diseases such as cancer, bacterial infections, metabolic disorders, and neurodegenerative conditions. These compounds act through various mechanisms, including enzyme inhibition, receptor modulation, and disruption of microbial and cancer cell pathways. Their structural flexibility allows for the design of novel molecules targeting specific therapeutic areas. The spotlight on these recent patents underscores oxadiazole derivatives’ growing importance in drug discovery, offering potential advancements in efficacy and safety for future therapeutic agents.

Heterocyclic compounds are the architects of modern medicinal chemistry, weaving intricate molecular frameworks that unlock the potential for life-saving therapies and transformative innovations.

1. Introduction

Oxadiazole is a class of heterocyclic aromatic chemical compounds belonging to the azole family with the molecular formula C₂H₂N₂O. These compounds are characterized by a five-membered ring containing two nitrogen atoms and one oxygen atom alongside two carbon atoms. First synthesized by Ainsworth in 1965, the calculated resonance energy of oxadiazole is 167.4 kJ/mol, and its thermal stability is enhanced with substitutions [1–4]. The four isomeric forms of the oxadiazole ring are 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, and 1,3,4-oxadiazole, each exhibiting distinct chemical and physical properties that have significant implications for their biological and industrial applications (Figure 1) [5,6].

Figure 1.

Structures of the regioisomeric oxadiazole rings.

According to the Web of Science data, the scientific attention on the application of 1,3,4-oxadiazoles has been continuously rising since the year 2000 (Figure 2) [7]. On the other hand, 1,2,5-oxadiazole derivatives have been found to be mainly used in high energy density materials (HEDMs) as well as biologically active compounds with cytotoxic properties [8–10]. Due to the instability and ring-opening of 1,2,3-oxadiazole heterocycle, resulting in substituted diazomethanes formation, this isomer of oxadiazole is the least of all explored [11]. The unique arrangement of atoms within the oxadiazole ring provides a foundation for a diverse array of chemical reactions and synthetic strategies [12]. The most common synthetic routes involve the cyclization of hydrazides with carboxylic acids, esters, or related derivatives. Such methodologies have been refined over the years, allowing for the efficient and scalable production of oxadiazole derivatives [13–15]. This structural versatility facilitates the design and synthesis of novel compounds tailored for specific functions, whether they be in pharmaceuticals, materials science, or agriculture. The structural configuration of oxadiazoles, particularly the presence of pyridine-type nitrogen atoms, facilitates strong interactions with various enzyme and receptor proteins in the human body. These interactions often result in significant biological effects, which can be harnessed for therapeutic purposes [16,17].

Figure 2.

Number of publications containing the keywords: “1,2,4-oxadiazole” (red), “1,2,5-oxadiazole” (blue), and “1,3,4-oxadiazole” (green) in their title since 1980 [7].

Oxadiazole derivatives have been incorporated into numerous synthetic compounds due to their high potency and therapeutic efficacy in treating various diseases and disorders [18–21]. The molecular architecture of oxadiazoles, including its isomers, is the most extensively studied due to their pronounced pharmacological properties [22]. These compounds have demonstrated a wide range of biological activities including antimicrobial [23,24], anti-inflammatory [25], analgesic [26,27], antifungal [28], antidepressant [29,30], antitubercular [31], anticonvulsant [32], anticholinesterase [33], antihypertensive [34,35], antidiabetic [36,37], antitumor/anticancer [38], antiviral [39], and antioxidant properties [40]. Additionally, oxadiazoles have found applications beyond pharmaceuticals; they have been employed in the creation of supramolecular liquid crystals [41] and high-energy density materials (HEDMs) [42], further demonstrating their utility in materials science. The presence of the oxadiazole ring in natural products, such as Phidianidine A and B, isolated from the sea slug Phidiana militaris, and Quisqualic acid from Quisqualis indica seeds, underscores the natural occurrence and biological relevance of this heterocycle [43,44]. Due to extensive biological effects, oxadiazole moiety has garnered attention from medicinal chemists and pharmacologists in their ongoing development and pharmacological assessment. Research on oxadiazoles has led to the development of compounds with enhanced pharmacological profiles and reduced toxicity. The continuous exploration of oxadiazole-based compounds aims to discover more potent and less toxic derivatives, contributing to the advancement of medical science and the development of new therapeutic agents Figure 3.

Figure 3.

Commercially available oxadiazole-based drugs.

Overall, oxadiazoles represent a versatile and valuable scaffold in medicinal chemistry, offering vast potential for the development of novel drugs and therapeutic strategies. Their extensive range of biological activities and the ongoing research into their applications highlight their significance in pharmaceutical research and drug development. This patent spotlight emphasizes the patents based on the diverse pharmacological properties that have been associated with and contributed to by substituted or derivatized oxadiazoles in the past five years (2020–2024).

2. Medicinal applications of oxadiazole derivatives (2020–2024)

The current patent spotlight addresses the recent breakthroughs of the oxadiazole derivatives with medicinal applications patented in 2020–2024. This study provides a summary of recently released patents on oxadiazole-based drugs, with the following objective of giving thoughts on how these scaffolds, as a privileged structure, could be used in the future (Table 1 and 2). We believe this article will be valuable to organic and medicinal chemists working on drug discovery and development and those interested in using them in chemistry and biology.

Table 1.

Patents based on 1,2,4-oxadiazole derivatives and their medicinal applications.

Patent no.	Structure	Biological activity/diseases	Tested organisms/cells	Mechanism of action/target	Ref.
WO2020060964		Anticancer	Various cancer cell lines	The compounds were tested for their ability to inhibit fibrinolysis. By affecting the activity of serine proteases, these compounds can potentially interfere with cancer progression and metastasis.	[45]
WO2020128675		Antitubercular	M. tuberculosis	Inhibition of critical bacterial enzymes, disruption of the bacterial cell wall or membrane.	[46]
WO2020064818		Anti-inflammatory	Lymphocytes	Sphingosine-1-phosphate receptor agonist, sequestering lymphocytes to peripheral lymphoid organs and away from their sites of chronic inflammation.	[47]
WO2020212513		Fungicidal activity	Fungi and fungal vectors of disease	Damaging cell membranes and inactivating enzymes and proteins. Hence, it interferes with energy production in fungi, which can lead to death.	[48]
WO2020245381		Histone deacetylase 6 (HDAC6) inhibitors	HDAC6 enzyme assay	Compounds were tested in in vitro HDAC6 cell-based assay and were found to inhibit the cellular activity of HDAC6.	[49]
WO2020211956		Antidiabetic agents	Free Fatty Acid Receptor 1 (FFAR1), also known as GPR40	The derivatives bind to the FFAR1 receptor, promoting insulin secretion only in the presence of high glucose levels, which makes them an ideal candidate for glucose-dependent diabetes treatment. It minimizes the risks associated with nonspecific insulin release.	[50]
WO2021173930		Neurodegenerative diseases	Tetracycline-inducible cell line (HEK-TREX)	To suppress excessive neuronal excitability and gain-of-function mutation in a gene (KCNT1).	[51]
WO2021081337		Anticancer	HTC116 cell line	These compounds are effective at inhibiting neoplastic cell growth. Ribonucleotide reductase (RR) is directly involved in neoplastic tumor growth and drug resistance.	[52]
WO2021105857		Meibomian gland dysfunction	Liver X receptors (LXRs)	The derivatives act as LXR agonists, triggering the activation of genes involved in cholesterol efflux, lipid synthesis, and anti-inflammatory pathways. This mechanism helps regulate lipid homeostasis in the meibomian glands, improving gland function and reducing symptoms of meibomian gland dysfunction (MGD). Additionally, the anti-inflammatory effects of LXR activation help manage chronic inflammation associated with the condition.	[53]
WO2022149925		Metabolic diseases	Tryptophan hydroxylase 1 (TPH1)	By inhibiting TPH1, these compounds decrease serotonin levels in peripheral tissues. This action does not affect the central nervous system, which may be advantageous for avoiding central side effects.	[54]
CN114195776		Anti-inflammatory	Farnesoid X receptor (FXR)	Oxadiazole derivatives are effective FXR agonists. These compounds can be used to treat a range of conditions by modulating bile acid, glucose, and lipid metabolism, as well as inflammation and liver fibrosis.	[55]
IN202321033845		Anticancer activity	HT29, MDA-MB-231, and A549 cell lines	Induction of cancer cell death, assessed by MTT assay and IC50 values calculation.	[56]
		Antimicrobial activity	E. coli, P. mirabilis, B. subtilis, and S. albus.	Interference with bacterial cell wall synthesis and replication
		Antifungal activity	Fungal strains, e.g., Candida albicans and Aspergillus niger	Disruption of fungal cell membrane integrity and function
US2023019648		Epilepsy (EIMFS)	Cell lines expressing KCNT1	Inhibition of KCNT1 potassium channel	[57]
		Neurological disorders associated with KCNT1 mutations	Various neuronal cell lines	Blockage of potassium channel leading to reduced neuronal excitability
US11952354		Anticancer	Various cancer cell lines (e.g., HeLa, MCF-7, A549, PC-3)	Induction of apoptosis, inhibition of cell proliferation, disruption of mitochondrial membrane potential	[58]
		Antimicrobial	Bacterial strains (e.g., S. aureus, E. coli) and fungal strains (e.g., C. albicans)	Inhibition of bacterial cell wall synthesis, disruption of microbial cell membranes
US11919871		Anticancer	Various cancer cell lines (e.g., HeLa, MCF-7, A549, PC-3)	Induction of apoptosis, inhibition of cell proliferation, disruption of mitochondrial membrane potential	[59]
		Antimicrobial	Bacterial strains (e.g., S. aureus, E. coli) and fungal strains (e.g., C. albicans)	Inhibition of bacterial cell wall synthesis, disruption of microbial cell membranes
WO2024028611		OCD symptom reduction	Rodent models of OCD (e.g., mice, rats). Neuronal cell lines (e.g., SH-SY5Y, HEK293).	Modulation of serotonin receptors (5-HT receptors). Dopamine receptors. Potential inhibition of enzymes involved in neurotransmitter metabolism (e.g., monoamine oxidase).	[60]
		General anxiety disorders	Models of anxiety-related behaviors. Cortical neurons are other relevant brain cell types.	Potential impact on GABAergic systems or other anxiety-related neurotransmitter systems.
EP2023069936		HDAC6 Inhibition	Recombinant HDAC6 enzyme	Selective inhibition of HDAC6 enzyme, affecting cellular processes like protein degradation and stress response	[61]
		Tubulin acetylation	697 human leukemia cells, murine neuroblastoma N2a cells, SH-SY5Y neuroblastoma cells.	Induction of tubulin acetylation, indicating effective inhibition of HDAC6. High activity was observed in most cell lines with various potencies.
EP2023076346		Fungicidal activity	Various fungal pathogens such as Puccinia recondita and Phakopsora pachyrhizi	Inhibits critical fungal biological processes	[62]
US2023076849		Antibacterial activity	C. difficile ATCC 43,255 strains	Bactericidal against vegetative cells, targets cell-wall synthesis	[63]

Table 2.

Patents based on 1,3,4-oxadiazole derivatives and their medicinal applications.

Patent no.	Structure	Biological activity/diseases	Tested organisms/cells	Mechanism of action/target	Ref.
WO2020030613		Anticancer	Various cancer cell lines	These oxadiazole derivatives specifically target the ATP binding site of the 6-phosphofructo-1-kinase (PFK-1) enzyme in cancer cells. By inhibiting this enzyme, the compounds reduce glycolytic activity, thereby decreasing NADH and lactate production. This reduction in lactate can potentially hinder the cancer cell’s ability to evade the immune system and reduce their capacity for angiogenesis and metastasis, making these compounds promising candidates for cancer therapy.	[64]
WO2020061216		Anticancer	Myeloid blood cells	A combination therapy for treating blood cancers, particularly acute myeloid leukemia (AML), using Axl kinase inhibitors and BCL-2 inhibitors. The synergy between these two types of inhibitors can improve treatment efficacy by simultaneously disrupting cancer cell survival mechanisms and promoting apoptosis.	[65]
WO2020219792		Antibacterial agents	S. aureus, MRSA, E. faecalis	Interference with bacterial cell wall synthesis. Inhibition of essential bacterial enzymes. Disruption of DNA/RNA synthesis or function.	[66]
WO2021070091		Neurodegenerative diseases	Muscarinic acetylcholine receptor M4	These derivatives function as M4 receptor agonists. These compounds are designed for the treatment of diseases mediated by the M4 receptor, including cognitive disorders, psychotic disorders, and potentially other related conditions.	[67]
CN113461630		Insecticidal agents	Binding assays and insect bioassays	The binding phase of the cartesian ketone derivative enhances its efficacy against insect pests.	[68]
CN113461631		Antiviral agents	Neuraminidase enzyme	The derivatives inhibit the neuraminidase enzyme, blocking the release of new viral particles from infected host cells. It halts viral replication and helps control infections, particularly in the treatment of influenza. The mode of action is based on binding to and inactivating neuraminidase, preventing the virus from detaching from the host cell.	[69]
WO2022029041		HDAC6-related diseases	Histone Deacetylase 6 (HDAC6)	These compounds are designed to selectively inhibit HDAC6, with potential applications in treating a variety of medical conditions, especially those related to inflammatory responses, cancer, and neurodegeneration.	[70]
WO2023244672		Enhancement of innate immune response	Human peripheral blood mononuclear cells (PBMCs), Mouse splenocytes	Stimulates immune cell activation; increases production of interferons and other cytokines.	[71]
		Viral replication inhibition	Human cell lines (e.g., HeLa, Vero cells)	Inhibits viral replication by enhancing immune response; potentially targets viral entry or replication pathways.
		Antiviral	Mouse models infected with various viruses (e.g., influenza, hepatitis)	Reduces viral load by boosting the body’s natural antiviral defenses; may involve modulation of immune signaling pathways.
US11998532		Antitubercular	Mycobacterium tuberculosis cultures. Animal models of tuberculosis (e.g., mice, rats).	Interference with bacterial cell wall synthesis. Inhibition of essential bacterial enzymes. Disruption of DNA/RNA synthesis or function.	[72]
WO2023224371		Neuroinflammatory diseases	NOX Enzyme	The oxadiazole derivative compounds inhibit NADPH oxidase (NOX) enzymes. NOX enzymes are involved in producing reactive oxygen species (ROS), which play a role in neuroinflammation. By inhibiting NOX2 and NOX4, these compounds reduce oxidative stress and inflammation in the brain.	[73]
IN202341033384		Anticancer activity	PC3, A549, MCF-7, DU-145	Inhibition of USP28‘s enzymatic activity leads to cell cycle arrest, apoptosis, inhibition of cell proliferation, anti-metastatic, and anti-angiogenic effects.	[74]
US2023/017894		Anticancer activity	Various cancer cell lines	Inhibition of HDAC6 induces cell cycle arrest apoptosis and also reduces tumor growth.	[75]
		Neurodegenerative diseases	Neuronal cell models	HDAC6 inhibition results in the reduction of protein aggregation and improves protein homeostasis
		Inflammatory disorders	Inflammatory cell models	HDAC6 inhibition modulates inflammatory pathways
IB2023050658		Pulmonary arterial hypertension	HPAECs, HPAECs under TGF-β stimulation, SD rats	Increasing acetylation levels at low compound concentrations improves cell viability and inhibits smooth muscle cell proliferation.	[76]
IB2023050659		Improved cardiac function	H9c2 cells, male rabbits, beagle dogs, Sprague-Dawley rats	Stabilizes microtubules, enhances ventricular function, reduces fibrosis, stabilizes Ca2+ transients, restores acetylated tubulin levels	[77]
US11958843		Antibacterial	Bacterial strains (e.g., S. aureus, E. coli, P. aeruginosa)	Inhibition of bacterial cell wall synthesis, disruption of bacterial cell membranes	[78]
		Antifungal	Fungal strains (e.g., C. albicans, A. niger)	Disruption of fungal cell membranes, inhibition of ergo sterol synthesis
WO2024054071		HDAC6-related diseases	Histone Deacetylase 6 (HDAC6)	By blocking HDAC6, these compounds affect the acetylation status of target proteins, leading to changes in gene expression and cellular functions.	[79]
KR2023013453		HDAC6 Inhibition	Human recombinant HDAC1 and HDAC6 enzymes	Inhibition of HDAC6 enzyme activity with high selectivity over HDAC1	[80]
IB2023057181		HDAC6 inhibition	In vitro with HDAC1 and HDAC6 enzymes	HDAC6 enzyme inhibition	[81]
		Neurodegenerative disease	Sprague-Dawley rat hippocampal neurons	Increased tubulin acetylation, improved mitochondrial transport

3. In-depth analysis

Over the past few years, oxadiazole derivatives have emerged as a pivotal class of heterocycles in medicinal chemistry, demonstrating exceptional versatility in drug design and development. Their rigid, electron-rich framework – particularly evident in the 1,3,4- and 1,2,4-oxadiazole isomers – has been central to the modulation of diverse biological targets, offering an ideal scaffold for structural manipulation. This review captures recent advances from 2020 to 2024, focusing on patented innovations that reflect a surge in interest toward oxadiazole-based pharmacophores. A comparative analysis of key patents reveals significant therapeutic relevance across multiple disease areas, including cancer, bacterial infections, neuroinflammation, and viral diseases such as influenza and SARS-CoV-2 (Table 3). The high prevalence of 1,3,4-oxadiazoles in clinical patent filings underscores their superior biological activity, which is often linked to favorable binding interactions with enzymes such as HDAC6, PFKFB3, neuraminidase, and Axl kinase. Synthetic strategies employed in these patents commonly involve facile ring closures, microwave-assisted synthesis, and strategic hybridization with pharmacophores like quinolones, benzimidazoles, or triazoles to boost efficacy and broaden pharmacological profiles.

Table 3.

Most impactful patents on oxadiazole derivatives.

Patent no.	Biological activity	Tested organisms/cells	Mechanism of action/target	Reference
WO2020060964	Anticancer	Various cancer cell lines	It inhibits fibrinolysis, affects serine protease activity, and potentially prevents metastasis.	[46]
WO2020128675	Antitubercular	Mycobacterium tuberculosis	It inhibits critical bacterial enzymes, disrupting bacterial cell walls/membranes.	[49]
WO2020211956	Antidiabetic	Free Fatty Acid Receptor 1 (FFAR1)	Enhances glucose-dependent insulin secretion, minimizing hypoglycemia risk.	[54]
WO2021081337	Anticancer	HTC116 cell line	It inhibits ribonucleotide reductase (RR), which is involved in tumor growth and drug resistance.	[57]
WO2021105857	Meibomian Gland Dysfunction	Liver X receptors (LXRs)	It acts as an LXR agonist, regulating lipid metabolism and inflammation in glands.	[59]
WO2022149925	Metabolic Diseases	Tryptophan hydroxylase 1 (TPH1)	Inhibits TPH1 to decrease peripheral serotonin, avoiding central nervous system side effects.	[62]
CN114195776	Anti-inflammatory	Farnesoid X receptor (FXR)	It modulates bile acid, glucose, and lipid metabolism, a potential treatment for liver fibrosis.	[63]
US2023019648	Epilepsy (EIMFS)	Cell lines expressing KCNT1	It inhibits the KCNT1 potassium channel, reducing neuronal excitability.	[70]
US11952354	Anticancer	HeLa, MCF-7, A549, PC-3 cell lines	Induces apoptosis, inhibits proliferation, and disrupts mitochondrial membrane potential.	[73]
US11952354	Antimicrobial	S. aureus, E. coli, C. albicans	It inhibits bacterial cell wall synthesis and disrupts microbial membranes.	[73]

Furthermore, the structure-activity relationship (SAR) findings across several patents elucidate how subtle substitutions significantly influence potency, selectivity, and ADME profiles. For instance, halogenation or alkyl substitution at the 2- or 5-positions of the oxadiazole ring can enhance lipophilicity and cell membrane penetration. At the same time, polar groups such as hydroxyl, methoxy, or sulfonamides contribute to increased hydrogen bonding with the target protein’s active site. In many cases, the incorporation of oxadiazole into molecular hybrids has been shown to result in dual or even multi-targeted activity, particularly valuable in managing multifactorial diseases such as cancer or type 2 diabetes. In silico docking and ADME/T predictions from various patents have provided additional support for these analogs, revealing excellent bioavailability, metabolic stability, and desirable pharmacokinetic properties.

Importantly, this review identifies several high-impact patents, which have been summarized in focused tables for clarity. These include compounds undergoing preclinical evaluation for HDAC6 inhibition with potential applications in neurodegenerative diseases, as well as oxadiazole-triazole hybrids that show broad-spectrum antiviral activity. The clinical relevance of these innovations is further underscored by their mechanism-driven design, low cytotoxicity profiles, and promising lead optimization data. Not only do these findings validate oxadiazoles as a privileged structure in drug discovery, but they also pave the way for future exploration of novel analogs using fragment-based or AI-guided design strategies. Collectively, the growing patent landscape reflects a paradigm shift toward oxadiazole-centered scaffolds as essential components in next-generation therapeutics, affirming their enduring value in medicinal and pharmaceutical chemistry.

4. Conclusion

The exploration of oxadiazole derivatives in recent years has solidified their position as a versatile and promising scaffold in medicinal chemistry. This patent spotlight showcases numerous derivatives that demonstrate potential across various therapeutic domains, including cancer, bacterial infections, metabolic diseases, and neurodegenerative disorders. Their structural versatility, coupled with strong interactions with biological targets, underlines their significance in drug discovery and development. Among the three classes of oxadiazole derivatives, the 1,3,4-oxadiazole scaffold emerges as the most promising for future research, owing to its broad-spectrum biological activities, favorable pharmacokinetic properties, and its versatile potential in the design of novel therapeutics targeting diverse diseases. The continuous emergence of patents in this domain, particularly from 2020 to 2024, highlights the growing interest and progress in tailoring oxadiazole-based compounds for targeted therapeutic applications while maintaining enhanced pharmacological and improved safety profiles.

5. Future perspectives

Looking ahead, the future of oxadiazole-based drug design lies in further refining their selectivity and reducing toxicity, ensuring that these compounds meet clinical efficacy and safety standards. The development of multi-targeted oxadiazole derivatives capable of addressing complex diseases, such as cancer and neurodegenerative disorders, could offer new avenues for therapeutic intervention. Advances in computational chemistry and high-throughput screening will likely play an instrumental role in identifying novel bioactive oxadiazole derivatives. Additionally, exploring the combination of oxadiazole scaffolds with other privileged structures could lead to the discovery of hybrid compounds with synergistic biological effects. The continued innovation in this field promises to shape the future landscape of medicinal chemistry, delivering more effective and safer treatments for a wide range of diseases.

Funding Statement

The work was funded by the Pakistan Academy of Sciences (PAS Project no. 111).

Article highlights

• Oxadiazoles are versatile heterocycles with broad biological activity, making them key in drug discovery.

• Patents from 2020–2024 reveal oxadiazole derivatives’ potential in treating cancer, infections, and neurodegenerative diseases.

• These compounds act via diverse mechanisms like enzyme inhibition and receptor modulation.

• The four oxadiazole isomers offer structural flexibility for designing targeted therapies.

• Scientific interest in 1,3,4-oxadiazoles has surged steadily since 2000.

• 1,3,4-Oxadiazoles stand out for their potent pharmacological profiles and drug-like properties.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

M Solangi and F Naz performed the literature survey, organized and sorted out the literature, and wrote their opinions. SA Ali and KM Khan conceived the idea of the opinion, supervised it, provided critical feedback, and finalized the article.

Financial disclosure

The authors also acknowledge the financial support of the Pakistan Academy of Science, 3-Constitution Avenue, G-5/2, Islamabad-44000, Pakistan, under PAS Project No. 111.

Information pertaining to writing assistance

The authors declare no conflict of interest, financial or otherwise. No writing assistance was utilized in the production of this manuscript.

Data sharing statement

Data will be available upon request.