1,3,4-Oxadiazole–sulfonamide hybrids: recent advances in biological activities, structure–activity relationships, and therapeutic applications

Abstract

Molecular hybridization has emerged as an effective strategy in medicinal chemistry for the development of multifunctional therapeutic agents with improved biological performance. Among the various hybrid scaffolds investigated, 1,3,4-oxadiazole–sulfonamide hybrids have gained considerable attention owing to the complementary pharmacological properties of both pharmacophores. The integration of the 1,3,4-oxadiazole nucleus and sulfonamide moiety within a single molecular framework has generated structurally diverse compounds exhibiting promising activities against a broad range of biological targets. This review provides a comprehensive overview of the biological activities and structure–activity relationships (SARs) of 1,3,4-oxadiazole–sulfonamide hybrids reported over the past two decades. Particular emphasis is placed on their antimicrobial, anticancer, anti-Alzheimer, anti-HIV, antidiabetic, anti-inflammatory, antioxidant, antimalarial, anti-glaucoma, and carbonic anhydrase inhibitory activities. Furthermore, the influence of key structural modifications on biological performance is critically discussed, highlighting the pharmacophoric features and substitution patterns associated with enhanced potency and selectivity. Collectively, the available evidence demonstrates the remarkable therapeutic versatility of 1,3,4-oxadiazole–sulfonamide hybrids and supports their continued exploration as promising scaffolds for future drug discovery and development.

Molecular hybridization has emerged as an effective strategy in medicinal chemistry for the development of multifunctional therapeutic agents with improved biological performance.

1. Introduction

The continuous emergence of drug resistance and the limited efficacy of many current therapies have intensified the search for novel bioactive scaffolds.¹ Molecular hybridization has emerged as one of the most effective strategies in modern medicinal chemistry, enabling the integration of two or more pharmacologically relevant motifs within a single molecular framework to enhance biological activity, improve selectivity, and optimize pharmacokinetic properties.^2,3

Among the diverse heterocyclic systems employed in drug discovery, the 1,3,4-oxadiazole nucleus has attracted considerable attention owing to its favorable physicochemical characteristics, metabolic stability, and broad spectrum of biological activities.^4,5 The presence of this privileged scaffold in several biologically active and clinically relevant compounds highlights its significance in medicinal chemistry.⁶ The clinical relevance of this scaffold is exemplified by several marketed drugs incorporating the 1,3,4-oxadiazole moiety (Fig. 1). Furthermore, numerous 1,3,4-oxadiazole derivatives have demonstrated promising antimicrobial, anticancer, antiviral, antidiabetic, anti-inflammatory, antimalarial, and neuroprotective activities, making this scaffold an attractive platform for the development of novel therapeutic agents.^7–9

Fig. 1. Representative marketed drugs containing the 1,3,4-oxadiazole scaffold and their therapeutic applications.

In parallel, sulfonamides are among the most successful pharmacophoric groups in medicinal chemistry and have maintained a central role in drug development for decades.^10,11 Their ability to participate in hydrogen-bonding interactions and establish favorable contacts within enzyme active sites has contributed to a wide range of therapeutic applications.^12,13 The therapeutic importance of sulfonamides is further evidenced by numerous clinically approved drugs containing this pharmacophore (Fig. 2). These examples underscore the remarkable pharmacological versatility and therapeutic value of sulfonamides.^14–16

Fig. 2. Representative clinically approved drugs containing the sulfonamide pharmacophore and their therapeutic indications.

The combination of 1,3,4-oxadiazole and sulfonamide motifs within a single molecular architecture has therefore emerged as an attractive strategy for developing multifunctional therapeutic agents. Such hybridization integrates the favorable biological and physicochemical attributes of both pharmacophores and frequently results in enhanced potency, improved selectivity, and broader pharmacological profiles.^17,18 Consequently, numerous 1,3,4-oxadiazole–sulfonamide hybrids have been synthesized and evaluated against a variety of biological targets, exhibiting promising antimicrobial, anticancer, anti-Alzheimer, antidiabetic, anti-HIV, anti-inflammatory, antioxidant, antimalarial, and carbonic anhydrase inhibitory activities.^19,20

Despite the growing number of studies reported in recent years, the available literature remains scattered across different therapeutic areas, and a dedicated review focusing specifically on the biological activities and structure–activity relationships of 1,3,4-oxadiazole–sulfonamide hybrids is still lacking. Although previous reviews have discussed oxadiazole-containing compounds or sulfonamide derivatives individually, the therapeutic potential, structural diversity, and SAR trends of their hybrid counterparts have not been systematically summarized.^5,7,15 Specifically, previous reviews addressing this chemical space have either focused broadly on 1,3,4-oxadiazole derivatives across diverse and unrelated chemical scaffolds without a dedicated focus on their sulfonamide-hybridized analogues,^5,7 or have addressed sulfonamide-based pharmacophores primarily in the context of carbonic anhydrase inhibition without covering the oxadiazole-linked hybrid architecture or its broader spectrum of reported biological activities.¹⁵ To the best of our knowledge, no prior review has systematically consolidated the structure–activity relationships of the 1,3,4-oxadiazole–sulfonamide hybrid scaffold specifically, across the ten distinct therapeutic activities addressed in the present work.

Therefore, the present review provides a comprehensive overview of the design, synthesis, biological evaluation, and structure–activity relationships of 1,3,4-oxadiazole–sulfonamide hybrids. Particular emphasis is placed on their diverse pharmacological activities and the key structural features governing their biological performance, aiming to provide valuable insights for the rational design of future therapeutic candidates.

2. Overview of the biological activities of 1,3,4-oxadiazole–sulfonamide hybrids

2.1. Anticancer activity

Cancer remains one of the leading causes of morbidity and mortality worldwide despite significant advances in diagnosis and treatment.^21,22 The ongoing emergence of drug resistance and the adverse effects of conventional chemotherapeutic agents have fueled the search for novel anticancer scaffolds with improved therapeutic profiles.^23,24

Among the investigated heterocyclic systems, 1,3,4-oxadiazole–sulfonamide hybrids have attracted considerable interest owing to their promising antiproliferative activity against various cancer cell lines,^25,26 consistent with the broader recognition of privileged nitrogen- and oxygen-containing heterocyclic cores as versatile scaffolds in rational anticancer drug design.²⁷ The anticancer potential of these hybrids has been linked to their ability to modulate diverse molecular targets and signaling pathways involved in tumor growth and progression.^28,29 Among these, the endothelin axis has emerged as an attractive therapeutic target due to its critical role in regulating cancer cell proliferation, migration, and tumor–stroma interactions.^30,31

Endothelin-1 (ET-1) signaling via ETA receptors plays a pivotal role in colorectal tumor progression, regulating proliferation, migration, and stromal interactions.³² Targeting ETA receptors with selective antagonists has emerged as a promising therapeutic strategy, aiming to disrupt tumor–stroma crosstalk and potentiate apoptosis.^33,34 In 2013, Haque et al.³⁵ investigated the anticancer effects of the ETA receptor antagonist zibotentan 1 (Fig. 3) on colorectal cancer cell lines (HT29, SW620) and primary colonic fibroblasts. ET-1 induced proliferation, migration, and contraction predominantly via the ETA receptor, which was effectively inhibited by zibotentan (IC₅₀: 0.1–1 µM). Preliminary SAR indicates that the oxadiazole–sulfonamide scaffold and heterocyclic substitutions in compound 1 enhance ETA selectivity and potency. Mechanistically, ET-1 effects involved EGF receptor transactivation, and zibotentan 1 potentiated apoptosis when combined with paclitaxel, highlighting stromal fibroblasts as critical therapeutic targets.

Fig. 3. Structure–activity relationship (SAR) of a new anticancer agent, 1,3,4-oxadiazole-based sulfonamide hybrids 1 and 2a–b.

After one year, Prasanna Kumar et al. in 2014 (ref. 36) synthesized a series of new 2,5-disubstituted-1,3,4-oxadiazoles and evaluated their in vitro antiproliferative activity against human cancer cell lines: K562, Colo-205, MDA-MB 231, and IMR-32 using the MTT assay. Among them, compounds 2a and 2b (Fig. 3) demonstrated the most potent activity across all tested lines, while other derivatives exhibited moderate inhibition. SAR analysis indicated that the presence of electron-withdrawing halogens (F, Cl) at para or meta positions significantly enhanced activity, whereas electron-donating methoxy groups decreased efficacy. These findings highlight the critical role of aryl substitution patterns in modulating antiproliferative potency, supporting further optimization of the oxadiazole–sulfonamide scaffold.

In addition, Gamal El-Din et al. in 2015 (ref. 17) synthesized a series of 1,3,4-oxadiazole derivatives bearing terminal sulfonamide moieties. Among this series, compounds 3a and 3b (Fig. 4) were identified as the most active. Compound 3a, with a p-chlorophenyl substituent on the oxadiazole ring and a p-methoxy benzenesulfonamide terminal group, exhibited broad-spectrum antiproliferative activity against leukemia (SR), melanoma (SK-MEL-5, UACC-257), and breast cancer (T-47D, MDA-MB-468) cell lines, with inhibition exceeding 80% at 10 µM. Furthermore, compound 3b, featuring a p-methoxyphenyl group on the oxadiazole ring and a p-chlorophenyl sulfonamide terminal group, showed significant activity against lung (NCI-H522) and breast cancer (T-47D, MDA-MB-468) cell lines. These results underline the importance of the substituted oxadiazole scaffold and aromatic sulfonamide moiety in enhancing anticancer potency.

Fig. 4. Structure–activity relationships (SAR) of 1,3,4-oxadiazole-based sulfonamide hybrids 3a–b and 4a–b as anticancer agents.

After a short gap, Szafrański et al. in 2020 (ref. 37) synthesized a series of (E)-5-((2-arylvinyl)-1,3,4-oxadiazol-2-yl) benzenesulfonamides, and evaluated their cytotoxic activity against human cancer cell lines MCF-7, HCT-116, and HeLa, as well as the noncancerous HaCaT line. Among these derivatives, compound 4a (Fig. 4), bearing a 5-nitrothiophene moiety and R₁ Cl, exhibited the most potent activity with IC₅₀ values of 0.5 µM (HCT-116), 4 µM (MCF-7), and 4.5 µM (HeLa). Compound 4b, containing a 5-nitrofuran substituent and R₁ SCH₂Ph, showed high selective activity against HCT-116 (IC₅₀ = 4 µM), demonstrating remarkable anticancer selectivity. Structure–activity analysis revealed that the introduction of nitro-substituted heterocycles at the aryl-vinyl position significantly enhances cytotoxicity, while the meta-position of the sulfonamide relative to the oxadiazole ring confers higher potency than the para-position or the absence of the sulfonamide moiety.

Ravula et al., 2022 (ref. 38) designed and synthesized a series of quinoxaline-1,3,4-oxadiazole sulfonamide hybrids, which were evaluated for in vitro anti-proliferative activity against human cancer cell lines HeLa, A549, MCF-7, and HEK-293 using the MTT assay, with etoposide as a reference drug. Among these derivatives, compound 5a (Fig. 5) demonstrated the highest potency across all tested cell lines, with IC₅₀ values of 1.25 µM (HeLa), 3.00 µM (A549), 4.30 µM (MCF-7), and 3.40 µM (HEK-293). In contrast, compound 5b and 5c exhibited slightly lower but still significant cytotoxicity. Structure–activity relationship analysis revealed that the introduction of electron-donating methoxy groups on the phenyl ring significantly enhances anticancer activity, whereas weaker donors such as methyl in the 2,4-positions reduce potency. Additionally, these compounds showed high inhibitory activity against tyrosine kinase EGFR, suggesting effective interaction with cancer-relevant signaling pathways.

Fig. 5. Structure–activity relationships (SAR) of 1,3,4-oxadiazole-based sulfonamide hybrids 5a–c and 6a–c as anticancer agents.

Recently, in 2025 Chander et al.²⁰ synthesized a series of 1,2,3-triazole, 1,3,4-oxadiazole, and benzenesulfonamide hybrids and evaluated their in vitro inhibitory activity against the cathepsin B enzyme. Among these derivatives, compound 6a (Fig. 5) exhibited the highest inhibition potential (76.64% at 10⁻⁸ M). In addition, compound 6b, and compound 6c demonstrated similarly high activity with 75.54% and 74.39% inhibition, respectively. Structure–activity relationship analysis indicated that the presence of electron-withdrawing halogen substituents significantly enhances cathepsin B inhibitory activity, whereas electron-donating or strongly withdrawing groups such as NO₂ showed lower activity. Docking studies confirmed the formation of multiple hydrogen bonds and pi-interactions with key amino acid residues in the enzyme active site, consistent with the observed experimental potency. ADMET predictions further suggested that compounds possess favorable oral drug-like properties according to Lipinski's rules.

Collectively, these studies indicate no unified electronic preference: electron-withdrawing halogens favored ETA- and nitro-heterocycle-driven cytotoxicity, whereas electron-donating methoxy groups were preferred in EGFR-directed quinoxaline hybrids, indicating that substitution effects are governed by the specific molecular target rather than by a general electronic rule.

2.2. Antimicrobial activity

Antimicrobial resistance has become a major global health concern, substantially limiting the effectiveness of currently available therapeutic agents and increasing the burden of infectious diseases.^39,40 Consequently, the discovery of new antimicrobial candidates with improved efficacy and reduced susceptibility to resistance mechanisms remains an important area of medicinal chemistry research.^41,42 In this regard, 1,3,4-oxadiazole–sulfonamide hybrids have emerged as promising scaffolds, prompting extensive investigations into their antibacterial and antifungal potential.^43–45

Therefore, G. C. Ramaprasad et al. in 2012 (ref. 46) synthesized a series of 5-(5′-fluoro-2′-methoxybiphenyl-3-yl)-1,3,4-oxadiazol-2-amine sulfonamide derivatives and evaluated their in vitro antibacterial and antifungal activities against Gram-positive (S. aureus, B. subtilis), Gram-negative (E. coli, P. aeruginosa) bacteria, and fungal strains (C. albicans, A. niger) using the cup-plate method. Among the series, compound 7a (Fig. 6) exhibited the highest antibacterial and antifungal activity, effectively inhibiting all tested bacterial strains and showing good antifungal activity. In contrast, compound 7b demonstrated strong antibacterial activity and moderate antifungal effects. Structure–activity analysis indicated that halogen substitution on the phenyl ring, particularly difluoro, significantly enhances antibacterial potency, and electron-withdrawing substituents confer higher efficacy than electron-donating groups.

Fig. 6. Structure–activity relationship (SAR) of a new antimicrobial agent, 1,3,4-oxadiazole-based sulfonamide hybrids 7a–b and 8a–b.

Building on the exploration of sulfonamide-based oxadiazoles, Dholaria et al. (2018)⁴⁷ synthesized a novel series of 2-((5-aryl-1,3,4-oxadiazol-2-yl)thio)-N-(4-(N-(pyridin-2-yl)sulfamoyl)phenyl)acetamide derivatives and evaluated their antimicrobial activity against Gram-positive (S. aureus, E. faecalis), Gram-negative (E. coli, P. aeruginosa), and fungal strains (C. albicans, A. niger). Compound 8a (Fig. 6) exhibited the most potent antibacterial activity, surpassing ciprofloxacin (MIC = 62.5 µg mL⁻¹) against several bacterial strains while maintaining notable antifungal activity. Compound 8b also displayed promising antibacterial and antifungal effects. SAR analysis revealed that electron-withdrawing substituents, particularly chloro and nitro groups at the ortho and para positions of the phenyl ring, enhanced antibacterial potency, whereas electron-donating groups such as methoxy afforded only moderate activity. Additionally, hydrophilic substituents positively influenced antifungal activity.

Exploring the antibacterial potential of novel oxadiazole derivatives, Aziz-ur-Rehman et al. in 2019 (ref. 48) synthesized a series of 1-{[4-({[5-substituted-1,3,4-oxadiazol-2-yl] sulfonyl} methyl) phenyl] sulfonyl}-3-methylpiperidine derivatives and evaluated their antibacterial activity against Gram-positive and Gram-negative bacterial strains. Among the tested compounds, 9a (Fig. 7) displayed the highest potency against S. typhi and E. coli (MIC = 9.11 and 8.79 µM, respectively), while 9b exhibited broad-spectrum antibacterial activity. SAR analysis revealed that electron-withdrawing substituents, particularly nitro groups, enhanced antibacterial potency, whereas electron-donating groups afforded only moderate activity. Moreover, ortho- and meta-substitution on the phenyl ring was generally favorable for activity.

Fig. 7. Structure–activity relationships (SAR) of 1,3,4-oxadiazole-based sulfonamide hybrids 9a–b and 10a–b as antimicrobial agents.

In a continuation of the antimicrobial investigations, Özkan and Demirci (2019)⁴⁹ synthesized a series of sulfonamide derivatives incorporating tetrazole and 1,3,4-oxadiazole moieties and evaluated their antimicrobial activity against various bacterial and fungal strains. Compound 10a (Fig. 7) exhibited the highest antibacterial potency, with inhibition zones of 37–41 mm and MIC values as low as 4.125 µg mL⁻¹, whereas 10b showed superior activity against Gram-negative bacteria along with notable antifungal efficacy. SAR analysis revealed that para-halogen substituents enhanced antibacterial activity, while methoxy-containing analogs displayed selective activity toward Gram-negative strains.

Further expanding the scope of sulfonamide-based 1,3,4-oxadiazole hybrids, Kavitha et al. (2019)⁵⁰ synthesized a series of cyclohexyl-substituted 1,3,4-oxadiazole–sulfonamide derivatives and evaluated their antimicrobial activity. Among the tested compounds, the derivative 11c (Fig. 8) exhibited the highest activity against P. aeruginosa (26 mm), while the compound 11a showed potent antibacterial and antifungal activities. Moreover, the derivative 11b demonstrated notable broad-spectrum antibacterial efficacy. SAR analysis revealed that electron-withdrawing substituents on the sulfonamide phenyl ring, particularly fluoro and nitro groups, enhanced antimicrobial activity, whereas methoxy- and methyl-substituted analogs displayed comparatively lower potency. Thus, fluorinated sulfonamide-bearing 1,3,4-oxadiazoles emerged as the most promising antimicrobial candidates in this series.

Fig. 8. Structure–activity relationships (SAR) of 1,3,4-oxadiazole-based sulfonamide hybrids 11a–c and 12a–c as antimicrobial agents.

In another notable contribution, Iqbal et al. (2020)⁵¹ synthesized a series of 5-{1-[(4-chlorophenyl) sulfonyl] piperidin-4-yl}-2-thio-substituted-1,3,4-oxadiazole derivatives and evaluated their antibacterial activity against several Gram-positive and Gram-negative bacterial strains. Compound 12c (Fig. 8) emerged as the most active derivative against S. typhi (MIC = 8.23 µM), whereas 12b exhibited superior activity against P. aeruginosa and S. aureus (MIC = 10.40 and 10.58 µM, respectively). Moreover, compound 12a displayed potent inhibition against B. subtilis (MIC = 8.95 µM). SAR analysis indicated that heterocyclic and halogenated substituents attached to the sulfur atom of the oxadiazole ring were beneficial for antibacterial activity, with the 1,3-dioxolane, 3-nitrobenzyl, and 2-chlorobenzyl moieties producing the most active derivatives.

In contrast to the anticancer series, antimicrobial potency showed a consistent preference for electron-withdrawing halogen and nitro substituents across six independent studies, making this the most electronically predictable activity class within the oxadiazole–sulfonamide scaffold.

2.3. Carbonic anhydrase inhibitory activity

Carbonic anhydrases (CAs) are a family of zinc-containing metalloenzymes that catalyze the reversible hydration of carbon dioxide to bicarbonate and protons.^52,53 These enzymes participate in numerous physiological processes, including pH regulation, respiration, electrolyte secretion, and metabolic homeostasis.^54,55 Owing to their diverse biological functions and the involvement of specific isoforms in disorders such as glaucoma, cancer, obesity, and neurological diseases, carbonic anhydrases have emerged as important therapeutic targets.^11,56 The sulfonamide pharmacophore represents the most established zinc-binding group in clinically used CA inhibitors, making oxadiazole–sulfonamide hybrids attractive candidates for the development of novel and selective CA-targeting agents.^57,58

Initial efforts toward the development of oxadiazole–sulfonamide-based carbonic anhydrase inhibitors were reported by Zareef et al. in 2006 (ref. 59) who synthesized a series of 1,3,4-oxadiazole-5-thiol derivatives incorporating substituted benzenesulfonamide moieties and evaluated their inhibitory activity against hCA I, hCA II, and the tumor-associated hCA IX isoforms. Among the investigated oxadiazole derivatives, compounds 13b and 13a (Fig. 9) exhibited the highest activity toward hCA IX with K_i values of 9.9 and 10.1 µM, respectively, while showed markedly lower affinity toward hCA I and hCA II. In contrast, the remaining oxadiazole analogues showed substantially weaker inhibition, highlighting the influence of structural modifications on isoform selectivity. These results identified the oxadiazole–sulfonamide scaffold as a promising framework for the development of selective carbonic anhydrase inhibitors.

Fig. 9. Structure–activity relationships (SAR) of 1,3,4-oxadiazole–sulfonamide hybrids as carbonic anhydrase inhibitors 13a–b, 14a–c, and 15.

Building upon earlier investigations, Bianco et al. in 2017 (ref. 60) designed and synthesized a series of N-acylbenzenesulfonamide dihydro-1,3,4-oxadiazole hybrids and evaluated their inhibitory activity against hCA I, hCA II, hCA IX, and hCA XII isoforms. Most derivatives displayed preferential inhibition toward the tumor-associated hCA XII isoform. Among the series, compound 14a (Fig. 9) exhibited the strongest hCA IX inhibition (K_i = 25.0 nM), while compounds 14b and 14c showed potent and selective inhibition of hCA XII with K_i values of 6.8 and 6.7 nM, respectively. Further investigation of the resolved enantiomers of 14a revealed enhanced hCA XII selectivity for the levorotatory form, highlighting the influence of stereochemistry on isoform selectivity and emphasizing the importance of both substitution pattern and stereochemical configuration in modulating carbonic anhydrase inhibition.

More recently, Bekircan et al. in 2025 (ref. 61) reported a series of benzene sulfonamide-based heterocyclic hybrids and evaluated their inhibitory activity against hCA I, hCA II, hCA IX, and hCA XII isoforms. Among the oxadiazole–sulfonamide derivatives, compound 15 (Fig. 9) emerged as the most potent hCA IX inhibitor with a K_i value of 12.4 nM, surpassing the reference inhibitor acetazolamide (K_i = 25.0 nM). Molecular docking studies revealed favorable interactions of 15 within the hCA IX active site, supporting its pronounced inhibitory activity and selectivity. The incorporation of triazole, oxadiazole, and sulfonamide pharmacophores within a single molecular framework was found to be beneficial for achieving potent and selective carbonic anhydrase inhibition.

The consistency of the CA-inhibitory SAR across three independent studies (compounds 13a–b, 14a–c, and 15) merits closer mechanistic discussion. In the primary sulfonamide-containing series, the sulfonamide group can coordinate directly to the active-site zinc ion the canonical mode of action shared by all clinically approved sulfonamide-based CA inhibitors, including acetazolamide. What distinguishes potency and, more importantly, isoform selectivity within this scaffold class is not the zinc-binding group itself but the structural elaboration distal to it, consistent with the well-established “tail approach” in CA inhibitor design: substituents and heterocyclic extensions attached via the oxadiazole linker project into isoform-specific hydrophobic or hydrophilic sub-pockets that differ between the ubiquitously expressed cytosolic isoforms (hCA I, II) and the tumor-associated membrane-bound isoforms (hCA IX, XII).

This explains why compound 14a achieved potent hCA IX inhibition while its resolved levorotatory enantiomer showed markedly improved hCA XII selectivity a stereochemical effect operating entirely outside the zinc-binding pharmacophore. Similarly, the superior potency of compound 15 (K_i = 12.4 nM against hCA IX, surpassing acetazolamide) reflects the combined contribution of the oxadiazole linker's rigidity and an additional triazole ring providing supplementary hydrogen-bonding and π-interactions within the enzyme's entrance channel, as supported by molecular docking. Collectively, these findings position the oxadiazole ring not merely as a passive spacer but as a geometrically optimal linker that holds the sulfonamide warhead at the correct distance and orientation for zinc coordination while leaving sufficient conformational and steric freedom in the distal aryl tail to drive isoform-selective drug design a principle of direct relevance to minimizing the off-target hCA I/II-related side effects (e.g., paresthesia, metabolic acidosis) associated with earlier non-selective sulfonamide CA inhibitors.

Taken together, the anticancer, antimicrobial, and carbonic anhydrase-inhibitory series illustrate a broader pattern within this scaffold class: electron-withdrawing substituents reproducibly enhance potency where the biological target engages the hybrid through direct electrophilic or zinc-coordinating interactions (antimicrobial activity, hCA active-site binding), whereas target-specific signaling pathway engagement (e.g., EGFR transactivation in anticancer hybrids) can favor electron-donating character instead, underscoring that the electronic requirements of this scaffold are dictated primarily by the nature of the target interaction rather than by the scaffold itself.

2.4. Anti-Alzheimer activity

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the leading cause of dementia worldwide.^62,63 It is characterized by progressive cognitive decline, memory impairment, and behavioral disturbances that significantly affect patients' quality of life.^64,65 One of the major pathological features of AD is the cholinergic deficit resulting from decreased acetylcholine levels in the brain.^63,66 Consequently, inhibition of acetylcholinesterase (AChE), the enzyme responsible for acetylcholine hydrolysis, remains one of the most established therapeutic strategies for symptomatic management of the disease.^67–69

In recent years, 1,3,4-oxadiazole and sulfonamide derivatives have attracted considerable attention in medicinal chemistry owing to their favorable pharmacological properties, structural versatility, and ability to interact with diverse biological targets.^70,71 Accordingly, numerous oxadiazole–sulfonamide hybrids have been designed and evaluated as potential anti-Alzheimer agents through the modulation of cholinesterase activity.

In 2018, Rehman and co-workers⁷² synthesized a series of piperidine-linked 1,3,4-oxadiazole derivatives containing sulfonamide and propanamide fragments and evaluated their acetylcholinesterase inhibitory activity as potential anti-Alzheimer agents. Most compounds exhibited moderate to excellent AChE inhibition. Among the synthesized analogs, compound 16c (Fig. 10) was identified as the most potent inhibitor with an IC₅₀ value of 3.64 µM, followed by compounds 16b (IC₅₀ = 5.76 µM), and 16a (IC₅₀ = 7.21 µM). Structure–activity relationship analysis suggested that electron-donating substituents on the terminal aromatic ring enhanced the inhibitory potency, whereas replacement with non-aromatic substituents led to diminished activity. Moreover, the most active compounds exhibited relatively low hemolytic effects, highlighting their potential as promising lead candidates for further development as anti-Alzheimer agents.

Fig. 10. Structure–activity relationships (SAR) of 1,3,4-oxadiazole-based sulfonamide hybrids 16a–c and 17a–b as anti-Alzheimer agents.

In the same year 2018, Rehman et al.⁷³ further expanded their work on oxadiazole-based anti-Alzheimer agents through the synthesis of a new series of sulfonamide-containing 1,3,4-oxadiazole–piperidine hybrids, which were evaluated for their acetylcholinesterase (AChE) inhibitory activity. Among the synthesized compounds, 17b (Fig. 10) exhibited the highest potency with an IC₅₀ value of 28.54 µM, followed by 17a with an IC₅₀ value of 47.69. Structure–activity relationship analysis revealed that the nature of the terminal aromatic amide tail played a crucial role in modulating activity. The p-ethyl-substituted derivative 17a showed improved inhibition compared with the unsubstituted analogues, while the compound 17b, bearing a 2-methyl-6-nitro substitution pattern, displayed the strongest activity, highlighting the favorable effect of electron-withdrawing groups and additional binding interactions within the enzyme active site. Molecular docking studies further supported the superior binding affinity of compound 17b toward AChE.

More recently, in 2020, Iqbal et al.⁵¹ reported a series of 1,3,4-oxadiazole–piperidine–sulfonamide hybrids, which were previously discussed for their antimicrobial activity. Since the parent scaffold was illustrated previously (Fig. 8), only the newly introduced N-substituents relevant to the anti-Alzheimer evaluation are listed in Table 1. The synthesized derivatives were further assessed for their acetylcholinesterase (AChE) inhibitory activity as potential anti-Alzheimer agents. Among the tested compounds, 12d, 12e, and 12f emerged as the most potent inhibitors, exhibiting IC₅₀ values of 47.23, 49.21, and 51.39 µM, respectively.

Table 1. Newly introduced N-substituents (R) and their corresponding acetylcholinesterase (AChE) inhibitory activities for the most active oxadiazole–piperidine–sulfonamide hybrids 12d–f.

Compound	Substituent (R)	AChE IC50 (µM)
12d	2-Bromobenzyl	47.23
12e	2-Chloroethyl	49.21
12f	2-Phenethyl	51.39

Therefore, structure–activity relationship analysis indicated that the nature of the N-substituent attached to the piperidine moiety played a crucial role in modulating AChE inhibition. Derivatives bearing moderately lipophilic aromatic substituents demonstrated superior activity, suggesting that an appropriate balance between hydrophobicity and steric bulk enhances binding affinity within the enzyme active site. Molecular docking studies further supported these observations, revealing favorable interactions of the most active compounds with key residues located in both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE.

This divergence merits closer mechanistic interpretation in light of AChE's dual-site architecture. AChE possesses a narrow, gorge-shaped active site comprising a catalytic active site (CAS) at its base and a peripheral anionic site (PAS) at its entrance, both pharmacologically exploitable. In the Rehman et al. series (16a–c), the enhanced potency conferred by electron-donating dimethyl/ethyl-substituted aromatic tails is consistent with favorable π-stacking or hydrophobic accommodation within the PAS, a shallow, aromatic-residue-lined pocket that tolerates bulky, electron-rich aryl groups; non-aromatic cyclohexyl substitution abolished this interaction, underscoring the PAS's requirement for planar aromatic character rather than generic lipophilicity.

In contrast, in the structurally related sulfonamide–piperidine hybrids (17a–b), the superior potency of 17b (bearing a 2-methyl-6-nitro substitution) suggests engagement of a more sterically constrained sub-pocket nearer the CAS, where a compact electron-withdrawing group provides an additional hydrogen-bond acceptor without steric clash. This is corroborated by the Iqbal et al. (2020) series (12d–f), where docking confirmed simultaneous CAS/PAS engagement by moderately lipophilic, sterically balanced N-substituents, yet with lower potency than 16c or 17b, reinforcing that excessive steric bulk reduces dual-site engagement. Collectively, these observations indicate that AChE inhibition within this scaffold is governed less by a uniform electronic rule than by how precisely the terminal substituent geometry complements the distinct steric and electronic demands of the CAS and PAS subsites.

2.5. Anti-diabetic activity

Diabetes mellitus remains one of the most prevalent metabolic disorders worldwide and is associated with severe long-term complications affecting multiple organ systems.^74–76 Among the available therapeutic approaches, inhibition of digestive enzymes such as α-amylase has proven effective in reducing postprandial hyperglycemia and improving glycemic control.^77,78 Owing to their favorable pharmacological characteristics, 1,3,4-oxadiazole-based sulfonamide hybrids have been investigated as potential α-amylase inhibitors, leading to the identification of several promising antidiabetic candidates.^8,79

The cyclohexyl-substituted 1,3,4-oxadiazole–sulfonamide scaffold previously discussed in the antimicrobial activity section (Fig. 8) was further investigated by Kavitha et al. (2019)⁵⁰ for its antidiabetic potential through α-amylase inhibition assays. Structural variations introduced into the side-chain substituent are summarized in Table 2. Among the synthesized derivatives, compound 11d emerged as the most potent α-amylase inhibitor with an IC₅₀ value of 2.34 µM, surpassing the reference drug acarbose (IC₅₀ = 2.53 µM). Compounds 11e, 11f, and 11g also exhibited promising inhibitory activity.

Table 2. Substituent patterns and α-amylase inhibitory activity (IC₅₀) of additional oxadiazole–sulfonamide hybrids 11d–g derived from the scaffold previously discussed in the antimicrobial activity section.

Compound	Substituent (R)	α-Amylase IC50 (µM)
11d	Indole	2.34
11e	Indoline	6.23
11f	6-Nitro indoline	6.59
11g	1-Benzhydryl piperazine	7.15

Furthermore, the structure–activity relationship analysis revealed that incorporation of fused heterocyclic systems significantly enhanced α-amylase inhibition, as evidenced by the superior activity of the indole-containing derivative 11d and the indoline analogues 11e and 11f. The presence of a nitro substituent on the indoline ring was well tolerated, maintaining potent activity in compound 11f. In contrast, derivatives bearing simple substituted phenyl groups generally displayed lower inhibitory potency. Additionally, the benzhydryl piperazine moiety in compound 11g contributed favorably to enzyme inhibition, highlighting the importance of bulky heterocyclic and aromatic functionalities for improved antidiabetic activity within this oxadiazole–sulfonamide series.

More recently, Khan et al. in 2023 (ref. 80) designed and synthesized a probenecid-derived oxadiazole–sulfonamide hybrid 18 (Fig. 11) through a molecular hybridization approach incorporating sulfonamide, 1,3,4-oxadiazole, and phthalimide pharmacophores within a single molecular framework. The synthesized compound was evaluated for its antidiabetic potential through α-amylase inhibition studies and exhibited potent activity with an IC₅₀ value of 10.60 µg mL⁻¹, comparable to that of the reference drug acarbose (IC₅₀ = 8.80 µg mL⁻¹). Molecular docking studies further demonstrated favorable interactions within the α-amylase active site, including hydrogen-bonding interactions with key amino acid residues and hydrophobic contacts that supported the observed inhibitory activity.

Fig. 11. Structure of compound 18 with key pharmacophoric features relevant to α-amylase inhibition.

From a structural perspective, the promising activity of 18 may be attributed to the synergistic contribution of its constituent pharmacophores. The sulfonamide moiety provides opportunities for hydrogen-bond formation, while the 1,3,4-oxadiazole ring acts as a bioisosteric linker that enhances molecular rigidity and binding affinity. In addition, the phthalimide fragment offers an extended aromatic surface capable of establishing favorable hydrophobic and π–π interactions within the enzyme binding pocket. Collectively, the integration of these pharmacophoric elements within a single hybrid scaffold highlights the potential of oxadiazole–sulfonamide-based molecular hybrids as promising candidates for antidiabetic drug development.

Taken together, the superiority of fused bicyclic heterocycles (indole, indoline) over simple substituted phenyl rings across this series suggests that α-amylase inhibition in oxadiazole–sulfonamide hybrids depends primarily on extended aromatic surface area rather than on electronic modulation of a single ring. This structural preference can be rationalized mechanistically: the α-amylase active-site cleft is lined predominantly with aromatic residues that engage inhibitors through π-stacking and CH–π interactions rather than through polar or electronic complementarity.

Fused bicyclic heterocycles such as indole and indoline present a larger, rigid aromatic surface than a monosubstituted phenyl ring, enabling more extensive π-stacking contacts irrespective of electron density, consistent with the retained potency of the nitro-substituted indoline analogue 11f. This is further supported by compound 18, whose extended phthalimide surface achieved potency (IC₅₀ = 10.60 µg mL⁻¹) approaching that of the structurally more complex, oligosaccharide-mimetic reference acarbose (IC₅₀ = 8.80 µg mL⁻¹), despite representing a smaller, more synthetically accessible pharmacophore, a promising feature from a translational standpoint, although in vivo efficacy and gastrointestinal tolerability for this class remain to be established.

2.6. Anti-HIV activity

Human immunodeficiency virus (HIV) remains a major global health challenge despite significant advances in antiretroviral therapy.^81–83 The continuous emergence of drug-resistant viral strains necessitates the development of new antiviral agents with improved efficacy and novel mechanisms of action.^84,85 Sulfonamide-containing compounds have attracted considerable interest in antiviral drug discovery, while the 1,3,4-oxadiazole nucleus is recognized as a versatile pharmacophore with diverse biological activities.^86,87

One of the earliest investigations of the anti-HIV potential of oxadiazole–sulfonamide hybrids was reported by Iqbal et al. in 2006 (ref. 88) who synthesized a series of primary and secondary benzenesulfonamides bearing a 2,5-disubstituted-1,3,4-oxadiazole moiety and evaluated their anti-HIV-1 activity. The compounds were screened against HIV-1 using the XTT assay in MT-4 cells. Among the tested derivatives, compound 19a (Fig. 12) emerged as the most active analogue, producing 62%, 21%, and 14% inhibition of viral replication at concentrations of 50, 25, and 5 µg mL⁻¹, respectively. In contrast, compound 19b was completely inactive. All evaluated compounds were essentially non-cytotoxic (CD₅₀ > 100 µg mL⁻¹), with the exception of 19a, which displayed moderate cytotoxicity (CD₅₀ = 67 µg mL⁻¹). Structure–activity relationship analysis suggested that the presence of a free mercapto (–SH) group at the 5-position of the oxadiazole ring and a free primary sulfonamide (–SO₂NH₂) moiety contributed favorably to antiviral activity, while substitution of these functionalities led to a marked reduction in potency.

Fig. 12. Representative anti-HIV oxadiazole–sulfonamide hybrids reported and their corresponding structure–activity relationship 19a–b and 20a–b.

Notably, the reported 62% inhibition for compound 19a corresponds to a single-concentration percentage measurement (at 50 µg mL⁻¹) rather than a calculated IC₅₀ value, and thus reflects a distinct type of potency metric from the IC₅₀-, K_i-, and MIC-based data reported for the other activity classes discussed in this review. This distinction is compounded by the compound's cytotoxicity profile: with a CD₅₀ of 67 µg mL⁻¹ falling within the same order of magnitude as its active concentration range (5–50 µg mL⁻¹), the relatively small difference between the CD₅₀ and the highest tested antiviral concentration indicates a limited cytotoxicity margin. The antiviral selectivity of 19a therefore remains difficult to quantify. Taken together, these observations indicate that the anti-HIV potential of the oxadiazole–sulfonamide scaffold, while encouraging, requires further optimization to improve antiviral potency and cytotoxicity.

In addition, Syed et al. in 2011 (ref. 89) synthesized a series of chiral sulfonamide-containing 5-benzylthio-1,3,4-oxadiazoles and evaluated their anti-HIV activity against HIV-1 and HIV-2 in MT-4 cells. Among the investigated analogues, compounds 20a and 20b (Fig. 12) displayed the most notable antiviral effects within the series, although their activities remained modest and were accompanied by low selectivity indices. Overall, the obtained results indicated that incorporation of a benzyl-thio substituent at the 5-position of the oxadiazole nucleus afforded only limited anti-HIV activity, highlighting the need for further structural optimization of this scaffold.

With only two early studies reporting modest, low-selectivity activity, this remains the least optimized activity class for the scaffold; the consistent requirement for both a free mercapto group and an unsubstituted sulfonamide suggest a narrow structural window that has not yet been systematically explored.

2.7. Other activities and preclinical investigations

Beyond their well-established antimicrobial, anticancer, antidiabetic, anti-Alzheimer, and anti-HIV activities, oxadiazole–sulfonamide hybrids have also been explored in several additional therapeutic and preclinical applications. Owing to the versatile pharmacological properties of both oxadiazole and sulfonamide pharmacophores, members of this class have demonstrated potential in diverse biological settings, including antiglaucoma, antimalarial, anti-inflammatory, and antioxidant studies. Furthermore, preclinical investigations addressing pharmacokinetic and metabolic behavior have provided valuable insights into their suitability for future drug development.

2.7.1. Antiglaucoma candidates

Among the various therapeutic applications of oxadiazole–sulfonamide hybrids, several compounds have been explored as carbonic anhydrase II inhibitors for glaucoma management.^90,91 In addition to their pharmacological evaluation, subsequent studies have focused on elucidating their pharmacokinetic behavior and metabolic fate to facilitate further preclinical development.

Khokhlov et al. in 2024 (ref. 92) investigated the pharmacokinetic behavior of 4-(5-methyl-1,3,4-oxadiazol-2-yl) benzenesulfonamide 21c (Fig. 13), a selective carbonic anhydrase II inhibitor under development as an antiglaucoma agent. Following topical ocular administration, 21c exhibited favorable pharmacokinetic properties, including prolonged systemic persistence and high relative bioavailability. The compound remained detectable in plasma and blood samples for an extended period, supporting its suitability for ophthalmic application and further preclinical development. These findings provided important information regarding the in vivo disposition of 21c and established the basis for subsequent metabolic investigations.

Fig. 13. Parent antiglaucoma candidate (21c) and its major (21a) and minor (21b) metabolites identified during pharmacokinetic studies.

Using the metabolites previously identified (Fig. 13), Khokhlov et al. (2024)⁹³ in a different study further evaluated the pharmacokinetic parameters of 21c and its major biotransformation products in rat plasma; they investigated the metabolic fate using HPLC-MS/MS analysis of biological samples obtained from experimental animals. The study identified two principal metabolites, namely the hydroxymethyl derivative 21a and the N-hydroxysulfonamide derivative 21b, formed through oxidation of the methyl group and N-hydroxylation of the sulfonamide moiety, respectively. Among the detected metabolites, compound 21a was recognized as the major metabolite and exhibited the highest plasma exposure and longest half-life.

The preservation of the sulfonamide pharmacophore in 21a suggested retention of the structural features required for carbonic anhydrase inhibition. These results provided valuable insights into the biotransformation pathways of 21c and supported its continued preclinical evaluation as a potential antiglaucoma agent.

Unlike the potency-driven SAR trends observed elsewhere, the antiglaucoma candidate 21c was evaluated primarily through pharmacokinetic and metabolic profiling rather than comparative inhibitory potency, underscoring that preclinical translation for this scaffold has progressed beyond in vitro screening for at least one CA-selective derivative a stage of development not yet reached by the majority of the discussed hybrids.

Mechanistically, this shift in evaluation focus reflects the maturity of 21c relative to the other hybrids discussed in this review: its retention of an unsubstituted methyl-oxadiazole–sulfonamide core, without bulky aryl extensions, minimizes off-target hCA I/II engagement while preserving zinc-binding affinity, a design choice favoring ocular bioavailability and systemic tolerability over the maximal in vitro potency pursued in earlier series (e.g., compound 15, Section 2.3). The identification of 21a as the major, pharmacophore-preserving metabolite further suggests that the scaffold's metabolic stability, rather than its raw inhibitory potency, is the more clinically decisive parameter for antiglaucoma translation.

2.7.2. Anti-inflammatory activity

Inflammation plays a central role in the progression of numerous pathological conditions, including autoimmune, infectious, and degenerative diseases.^94–98 Consequently, considerable efforts have been directed toward the development of novel anti-inflammatory agents, among which oxadiazole–sulfonamide hybrids have emerged as promising candidates.

The cyclohexyl-substituted 1,3,4-oxadiazole–sulfonamide scaffold previously described in the antimicrobial activity section (Fig. 8) was also evaluated by Kavitha et al. in 2019 (ref. 50) for its in vitro anti-inflammatory activity using the bovine serum albumin (BSA) denaturation assay. Among the tested derivatives, compounds 11i, 11j, and 11k exhibited the most potent activity, with IC₅₀ values of 110, 110, and 111 µg mL⁻¹, respectively, surpassing the reference drug diclofenac (IC₅₀ = 157 µg mL⁻¹). In addition, compound 11h also demonstrated notable inhibitory effects with an IC₅₀ value of 118.2 µg mL⁻¹ (Table 3).

Table 3. Substituent patterns and anti-inflammatory activities of the most active cyclohexyl-substituted 1,3,4-oxadiazole–sulfonamide hybrids 11h–k.

Compounds	Substituent (R)	BSA denaturation assay IC50 (µg mL−1)
11h	4-Methylphenyl	118.2
11i	3-Methoxyphenyl	110.0
11j	4-Chlorophenyl	110.0
11k	4-Bromophenyl	111.0

Structure–activity relationship analysis suggested that both electron-donating and electron-withdrawing substituents on the sulfonamide phenyl ring were well tolerated; with no clear dependence on substituent position: the most active analogues combined one meta-substituted (3-methoxyphenyl, 11i) and two para-substituted (4-chlorophenyl, 11j; 4-bromophenyl, 11k) derivatives, all achieving comparable potency (IC₅₀ = 110–111 µg mL⁻¹). This indicates that the overall bulk and moderate polarizability of the substituent, rather than its precise ring position or electronic character, plays the more decisive role in enhancing anti-inflammatory activity within this oxadiazole–sulfonamide framework.

Unlike the antimicrobial and antioxidant series, both electron-donating and electron-withdrawing para-substituents performed comparably well, indicating that anti-inflammatory potency in this scaffold is governed primarily by substituent bulk and moderate polarizability rather than by a strict positional (para vs. meta) or electronic rule. This positional dependence is consistent with the proposed mechanism of BSA-denaturation inhibition, which relies on the compound occupying a hydrophobic surface groove on the protein rather than forming a specific hydrogen-bonded or electrostatic interaction; under such a binding mode, steric accessibility conferred by the para (or, less commonly, meta) position outweighs the electron-donating or -withdrawing character of the substituent itself.

2.7.3. Antimalarial activity

Malaria remains a major global health challenge, necessitating the continuous development of new chemotherapeutic agents.^99,100 In this context, oxadiazole–sulfonamide hybrids have attracted attention as potential antimalarial candidates due to their ability to interfere with essential parasite metabolic processes and heme detoxification pathways.

Zareef et al. in 2007 (ref. 101) synthesized a series of amino acid-derived oxadiazole–sulfonamide hybrids and evaluated their antimalarial activity using hemoglobin proteolysis and heme crystallization inhibition assays. Among the oxadiazole-containing derivatives, compounds 22b, 22a, and 22c (Fig. 14) exhibited the most promising activity, showing inhibition percentages of 38.16%, 36.05%, and 34.15%, respectively. These results demonstrated that incorporation of the 1,3,4-oxadiazole ring retained appreciable antimalarial activity within the sulfonamide series.

Fig. 14. Representative antimalarial oxadiazole–sulfonamide hybrids reported and their corresponding structure–activity relationship 22a–c.

Therefore, structure–activity relationship analysis indicated that both the nature of the amino acid-derived side chain and the substitution pattern on the sulfonamide phenyl ring influenced activity. In particular, derivatives bearing branched chiral side chains showed superior potency, while replacement of the p-methyl group with chlorine was generally well tolerated, highlighting the contribution of hydrophobic aromatic substitution to antimalarial activity.

The consistent tolerance for both chloro and methyl substitution alongside a strong preference for branched chiral side chains suggests that antimalarial activity in this series is driven primarily by steric/stereochemical complementarity with the parasite target rather than by electronic tuning of the aryl ring. This steric/stereochemical dependence is consistent with the proposed mode of action, which involves interference with hemoglobin proteolysis and heme crystallization within the parasite's digestive vacuole, a process governed by three-dimensional complementarity to parasite-derived enzymes and heme aggregates rather than by classical hydrogen-bonding or electronic pharmacophore models, explaining why chirality and branching, rather than electronic character, emerge as the dominant structural determinants in this series.

2.7.4. Antioxidant activity

Oxidative stress is implicated in the pathogenesis of numerous chronic diseases, prompting the search for novel antioxidant agents.^102–104 Therefore, the identification of effective antioxidant agents remains an important area of medicinal chemistry research, leading to the evaluation of oxadiazole–sulfonamide hybrids for their radical scavenging potential.^105,106

In 2015, Padmaja et al.¹⁰⁷ synthesized a series of sulfonamide-linked bis(1,3,4-oxadiazole) derivatives and evaluated their antioxidant activity using DPPH, nitric oxide (NO), and hydrogen peroxide (H₂O₂) scavenging assays. Among the oxadiazole–sulfonamide analogues, compound 23b (Fig. 15) emerged as the most potent antioxidant, exhibiting IC₅₀ values of 32.42, 30.28, and 30.97 µg mL⁻¹ in the DPPH, NO, and H₂O₂ assays, respectively, comparable to or slightly superior to ascorbic acid. Compound 23a also demonstrated notable radical scavenging activity, whereas the chloro-substituted analogue 23c showed reduced potency.

Fig. 15. Representative antioxidant oxadiazole–sulfonamide hybrids 23a–c and key SAR features associated with enhanced radical scavenging activity.

Structure–activity relationship analysis revealed that oxadiazole-containing derivatives displayed superior antioxidant activity compared with the corresponding thiadiazole and triazole analogues. Furthermore, sulfonamide-linked bis(oxadiazoles) showed higher radical scavenging activity than the corresponding sulfone-linked derivatives. Among the investigated substituents, the p-methyl-substituted analogues exhibited the highest activity, whereas p-chloro substitution resulted in a marked reduction in antioxidant potency.

The clear preference for electron-donating p-methyl substitution, in contrast to the antimicrobial trend, provides the clearest evidence within this review that electronic effects are not merely target-dependent but can act in opposite directions across activities, reinforcing the need for target-specific rather than scaffold-wide design rules. This electron-donating preference is mechanistically consistent with radical-scavenging assays (DPPH, NO, H₂O₂), which favor substituents capable of stabilizing the resulting radical intermediate through resonance or hyper-conjugative electron donation; electron-withdrawing chloro substitution, in contrast, destabilizes the transition state for hydrogen-atom or electron transfer, rationalizing the inverse trend relative to the antimicrobial and anticancer series discussed earlier.

2.8. Overall structure–activity relationship trends

Beyond the activity-specific trends discussed above, the accumulated SAR data can be reorganized around five distinct structural positions within the oxadiazole sulfonamide scaffold, each governing a partially independent set of biological outcomes (Fig. 16). This position-based organization highlights that substituent effects rarely generalize across the whole molecule or across all therapeutic activities; rather, each site the aryl ring flanking the oxadiazole, the linker bridging the two pharmacophores, the terminal sulfonamide nitrogen, additional fused heterocyclic extensions, and the stereochemical configuration of side chains impose its own, often target-specific, structural requirements.

Fig. 16. Summary of structure–activity relationship (SAR) trends of oxadiazole–sulfonamide hybrids across different therapeutic applications.

To complement this positional analysis with direct quantitative evidence, Table 4 summarizes the most potent compound identified within each therapeutic activity alongside its reported potency and principal SAR determinant.

Table 4. Summary of the most potent 1,3,4-oxadiazole–sulfonamide hybrids reported within each surveyed therapeutic activity, with corresponding potency and key structure–activity determinant^a.

Therapeutic activity	Best compound	Potency	Reference drug comparison	Key SAR feature
Anticancer	4a	IC50 = 0.5 µM (HCT-116)	—	Nitro-heterocycle at aryl-vinyl position; meta-sulfonamide positioning
Antimicrobial	10a	MIC = 4.125 µg mL−1	—	Para-halogen substitution; EWG-favored
Carbonic anhydrase (hCA IX)	15	K i = 12.4 nM	Superior to acetazolamide (Ki = 25.0 nM)	Combined triazole–oxadiazole–sulfonamide framework
Anti-Alzheimer (AChE)	16c	IC50 = 3.64 µM	—	EDG on terminal aromatic ring
Anti-diabetic (α-amylase)	11d	IC50 = 2.34 µM	Superior to acarbose (IC50 = 2.53 µM)	Indole-fused heterocyclic tail
Anti-HIV	19a	62% inhibition (50 µg mL−1)	—	Free –SH and free primary sulfonamide required
Antiglaucoma	21c	Favorable ocular bioavailability & sustained systemic persistence (PK study, not a potency IC50/Ki)	—	CA II-selective sulfonamide; oxadiazole methyl group retained on major metabolite
Anti-inflammatory	11i/11j	IC50 = 110.0–111.0 µg mL−1	Superior to diclofenac (IC50 = 157 µg mL−1)	Substituent bulk/polarizability rather than ring position
Antimalarial	22b	38.16% inhibition	—	Branched chiral amino acid side chain
Antioxidant	23b	IC50 = 30.3–32.4 µg mL−1 (DPPH/NO/H2O2)	Comparable to ascorbic acid	p-Methyl (EDG); sulfonamide-linked bis(oxadiazole)

^aValues expressed as % inhibition at a single, specified concentration (compounds 19a and 22b) reflect a fundamentally different potency metric from concentration-response-derived IC₅₀, K_i, and MIC values and should not be directly compared with the latter across rows.

3. Conclusion and future perspectives

This review highlights the therapeutic potential of oxadiazole–sulfonamide hybrids as versatile bioactive scaffolds with promising applications in medicinal chemistry. The collected studies demonstrate that structural modifications around both the oxadiazole and sulfonamide pharmacophores profoundly influence biological activity and target selectivity. SAR studies discussed throughout this review revealed the importance of the 1,3,4-oxadiazole ring as a privileged scaffold for target binding, while the sulfonamide moiety contributes significantly to molecular recognition and biological activity. In many cases, electron-withdrawing substituents, particularly halogens, enhanced biological potency, whereas the influence of electron-donating groups was found to be target-dependent. Furthermore, incorporation of additional heterocyclic, aromatic, and bulky hydrophobic fragments frequently improved activity and selectivity.

Despite the extensive structural diversity surveyed in this review, the translational impact of current research on this scaffold class remains constrained by several interconnected methodological gaps. The pronounced target-dependence of substituent effects observed throughout this review where the same electronic or steric modification can enhance one activity while diminishing another argues against continued single-target optimization campaigns, pointing instead toward systematic, standardized cross-target profiling of new derivatives as a more reliable route to generalizable design principles.

Selectivity remains a particularly underexplored dimension in this respect: with the exception of the carbonic anhydrase series, where isoform selectivity (hCA IX/XII versus hCA I/II) was systematically addressed, most surveyed studies report potency against a single target or cell line without evaluating off-target engagement, leaving the translational risk of promiscuous binding largely unassessed across this scaffold class. This need is compounded by the overwhelming reliance on in vitro evaluation across nearly all reported series, which remains a major translational bottleneck; broader application of in vivo pharmacokinetic, toxicological, and efficacy studies is still required before the promising in vitro potency documented here can be meaningfully extrapolated toward clinical relevance.

At the same time, the several decades of structurally diverse but inconsistently benchmarked data accumulated for this hybrid class make it a natural candidate for more advanced investigative approaches, including high-throughput screening platforms, artificial intelligence and machine learning-assisted SAR modeling, and refined computational and instrumental techniques for target validation tools that could help resolve conflicting substituent trends and guide synthetic efforts more efficiently than sequential empirical screening alone. Addressing these interconnected gaps would allow the considerable structural versatility documented here to translate more effectively into clinically viable candidates.

Conflicts of interest

There are no conflicts to declare.

Abbreviations

AChE

Acetylcholinesterase

AD

Alzheimer's disease

BSA

Bovine serum albumin

CA

Carbonic anhydrase

CAS

Catalytic active site

CD₅₀

50% cytotoxic concentration

DPPH

2,2-Diphenyl-1-picrylhydrazyl

EGFR

Epidermal growth factor receptor

ETA

Endothelin receptor type A

ET-1

Endothelin-1

hCA

Human carbonic anhydrase

HIV

Human immunodeficiency virus

HPLC–MS/MS

High-performance liquid chromatography–tandem mass spectrometry

IC₅₀

Half-maximal inhibitory concentration

K _i

Inhibition constant

MIC

Minimum inhibitory concentration

MTT

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NO

Nitric oxide

PAS

Peripheral anionic site

SAR

Structure–activity relationship

XTT

2,3-Bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide

Cell lines

A549

Human lung adenocarcinoma cell line

HCT-116

Human colorectal carcinoma cell line

HEK-293

Human embryonic kidney 293 cell line

HeLa

Human cervical carcinoma cell line

K562

Human chronic myelogenous leukemia cell line

MCF-7

Human breast adenocarcinoma cell line

SW620

Human colorectal adenocarcinoma cell line

Data availability

The data supporting this article have been included in the manuscript.