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  • A Review on the Synthesis, Characterization, and Pharmacological Applications of Thiadiazole Derivatives

  • Photo Dr. Sanjay Kumar Kushwaha* Photo Vipul Singh

  • Bhavdiya Institute of Pharmaceutical Sciences and Research, Sebar Sohawal, Ayodhya, UP 224126    

Abstract

Thiadiazoles, a class of five membered heterocycles containing two nitrogen atoms and one sulfur atom, have attracted sustained interest over the past three decades owing to their rich chemistry and diverse biological activities. This review critically examines the state of the art synthetic strategies for 1,2,3 and 1,3,4 thiadiazoles, outlines modern spectroscopic and analytical techniques employed for their structural elucidation, and summarizes the pharmacological profile of these scaffolds in antimicrobial, anti inflammatory, anticancer, antiviral, and central nervous system (CNS) domains. Emphasis is placed on structure activity relationship (SAR) trends, the impact of hetero atom substitution, and the emergence of hybrid thiadiazole based pharmacophores. The review concludes with a discussion of current challenges and prospective directions for the rational design of thiadiazole containing drug candidates.

Keywords

Thiadiazole, heterocycle, synthesis, characterization, pharmacology, SAR

Introduction

The thiadiazole nucleus, comprising a fused arrangement of sulfur and nitrogen atoms within a five?membered aromatic ring, represents a privileged scaffold in medicinal chemistry. Among its isomers, 1,2,3?thiadiazole and 1,3,4?thiadiazole are the most extensively explored due to their synthetic accessibility and amenability to functional diversification. Early pharmacological investigations demonstrated that simple thiadiazole derivatives exhibit potent antimicrobial and anti?inflammatory effects, prompting a surge of synthetic efforts aimed at expanding the chemical space around this heterocycle.[1-3] Advances in modern organic synthesis—namely transition?metal?catalyzed cross?coupling, multicomponent reactions, and green protocols—have enabled rapid construction of highly substituted thiadiazoles with fine?tuned physicochemical properties. Concurrently, powerful spectroscopic tools (NMR, HR?MS, X?ray crystallography, FT?IR) and computational methods have facilitated unambiguous structural assignment and insight into electronic characteristics that govern biological activity.

Given the breadth of recent publications and the evolving therapeutic relevance of thiadiazole?based molecules, a comprehensive review that integrates synthetic methodology, analytical characterization, and pharmacological evaluation is timely. This article aims to (i) catalogue contemporary synthetic routes, (ii) summarize key characterization techniques, (iii) collate reported biological activities, (iv) discuss SAR patterns, and (v) highlight prospective research avenues.

Chemical Overview of Thiadiazoles

 

Isomer

Structural Formula

Aromaticity

Key Reactivity

Representative Applications

1,2,3?Thiadiazole

[1,2,3?thiadiazole]

Aromatic (6?π?electron)

Electrophilic substitution at C?5; nucleophilic attack at C?4

Antifungal agents, herbicides

1,3,4?Thiadiazole

[1,3,4?thiadiazole]

Aromatic (6?π?electron)

Electrophilic substitution at C?5; facile N?oxidation

Antibacterial, anti?inflammatory, anticancer

 

Both isomers possess a planar geometry and are characterized by a pronounced electron?deficient aromatic system, which enhances binding to biological macromolecules (e.g., enzymes, receptors). The sulfur atom contributes to polarizability, facilitating interactions such as hydrogen?bond acceptance and π?stacking.

Synthetic Strategies

  1. Classical Approaches
  1. Condensation of Amidines with Carbonyl Sulfide (CS?): The pioneering route to 1,3,4?thiadiazoles involves the reaction of amidines (R?C(=NH)NH?) with CS? under basic conditions, generating a dithiocarbamate intermediate that cyclizes upon heating [4].
  2. Oxidative Cyclization of Thiosemicarbazides: 1,2,3?Thiadiazoles can be obtained by treating thiosemicarbazides with bromine or N?bromosuccinimide (NBS) in acetic acid, effecting intramolecular S?N bond formation [5].

These methodologies, while robust, often require harsh reagents and provide limited substitution patterns.

  1. Modern Synthetic Paradigms

 

Method

Representative Reaction

Advantages

Representative Products

Microwave?Assisted Cyclization

Thiosemicarbazide + aldehyde → 1,2,3?thiadiazole (10?min, 120?°C)

Reduced reaction time, improved yields

5?aryl?1,2,3?thiadiazoles

Transition?Metal?Catalyzed Cross?Coupling

2?Halothiadiazoles + organoboron reagents (Suzuki) → 5?aryl?1,3,4?thiadiazoles

Broad substrate scope, mild conditions

5?phenyl?1,3,4?thiadiazole

Multicomponent Reactions (MCRs)

Amine + aldehyde + CS? + oxidant → 1,3,4?thiadiazole

One?pot, atom?economical, diverse functionality

2?aryl?5?substituted?1,3,4?thiadiazoles

Green Solvent/solvent?free protocols

Ball?milling thiosemicarbazide + acid catalyst → 1,2,3?thiadiazole

Sustainable, scalable

5?alkyl?1,2,3?thiadiazoles

Photochemical Cyclization

Visible?light mediated radical cyclization of thiohydrazides → 1,3,4?thiadiazoles

Mild, metal?free, functional?group tolerant

5?alkoxy?1,3,4?thiadiazoles

 

  1. Microwave?Assisted Synthesis

The microwave?assisted cyclization of thiosemicarbazides with aldehydes or ketones (in the presence of an acid catalyst such as p?toluenesulfonic acid) yields 5?substituted 1,2,3?thiadiazoles within minutes. Reaction optimization typically involves a temperature of 120–140?°C, a power setting of 300?W, and a reaction time of 5–15?min [6]. This protocol dramatically reduces side?product formation and facilitates rapid library generation for SAR studies.

  1. Suzuki–Miyaura Cross?Coupling

Halogenated 1,3,4?thiadiazoles (e.g., 5?bromo?1,3,4?thiadiazole) serve as versatile electrophiles in Suzuki couplings with aryl? or heteroaryl?boronic acids. Palladium catalysts such as Pd(PPh?)?, combined with bases (K?PO? or Cs?CO?) in dioxane/water mixtures, afford high yields (>80?%) of 5?aryl?1,3,4?thiadiazoles [7]. The methodology enables incorporation of pharmaceutically relevant moieties (e.g., heterocycles, fluorinated phenyls) that modulate lipophilicity and metabolic stability.

  1. Multicomponent Reactions

A three?component condensation comprising amidines, aldehydes, and CS? in the presence of an oxidant (e.g., iodine) furnishes 1,3,4?thiadiazoles in a single pot. The reaction tolerates a wide range of aldehydes (aryl, heteroaryl, aliphatic) and yields products bearing diverse substituents at C?5 and N?2 positions, which are crucial for activity tuning [8].

  1. Green Chemistry Approaches

Mechanochemical synthesis via ball?milling of thiosemicarbazides with acetic acid under solvent?free conditions has emerged as an environmentally benign route to 1,2,3?thiadiazoles, delivering yields up to 92?% while eliminating organic solvents and reducing waste [9].

  1. Photoredox?Catalyzed Cyclization

Visible?light photocatalysis employing Ir? or Ru?based complexes enables radical cyclization of N?aryl thiohydrazides to yield 1,3,4?thiadiazoles under ambient temperatures. This metal?mediated protocol exhibits excellent functional?group tolerance, allowing incorporation of sensitive moieties such as nitro or cyano groups [10].

  1. Stereoelectronic Considerations

The electron?deficient nature of the thiadiazole core facilitates nucleophilic substitution at C?5, enabling post?synthetic diversification via SNAr or Michael-type addition. Moreover, oxidation of the sulfur atom to the sulfone or sulfoxide can modulate pharmacokinetic parameters (e.g., solubility, metabolic stability) and is frequently employed in lead optimization [11].

Structural Characterization

Accurate structural elucidation is indispensable for confirming the integrity of thiadiazole derivatives, especially when subtle isomeric differences affect bioactivity.

 

Technique

Information Gained

Typical Observations for Thiadiazoles

¹H NMR

Proton environment, substitution pattern

Aromatic protons (δ?6.8–8.2?ppm); absence of signals for C?5 H in fully substituted derivatives

¹³C NMR

Carbon framework, quaternary carbons

Downfield signals for C?2/C?5 (δ?150–165?ppm) due to hetero?atom deshielding

²D NMR (HSQC, HMBC)

Correlation of H–C, long?range couplings

HMBC cross?peaks linking C?5 to aromatic protons confirm substitution

IR Spectroscopy

Functional groups, S?N stretch

Characteristic C=S stretching at ~1060?cm?¹; N?S vibrations ~950?cm?¹

HR?MS (ESI/CI)

Molecular weight, isotopic pattern

Molecular ion peaks consistent with C/H/N/S composition; sulfur isotopic signature (??S/³²S)

X?ray Crystallography

Unambiguous 3?D arrangement, bond lengths

S?N bond lengths ≈?1.62?Å; planar heterocycle with bond angles ≈?120°

DFT Calculations

Electronic distribution, HOMO?LUMO gap

Frontier orbitals localized on C?5 and hetero?atoms; gap ~?3.2?eV (indicative of aromaticity)

 

In a case study the crystal structure of 5?(4?chlorophenyl)-1,3,4?thiadiazole (C?H?ClN?S) revealed a C?S bond length of 1.704?Å, confirming partial double?bond character, which correlates with its enhanced binding affinity toward bacterial dihydropteroate synthase [12].

Pharmacological Applications       

Thiadiazole derivatives have been investigated across a spectrum of therapeutic areas. The following sections summarize key findings, grouped by activity class, together with representative compounds and SAR insights.

Antimicrobial Activity

  1. Antibacterial: 1,3,4?Thiadiazoles bearing electron?withdrawing substituents (e.g., nitro, halogen) at C?5 exhibit potent inhibition of Gram?positive bacteria (MIC?=?0.5–2?µg?mL?¹). SAR indicates that a para?chlorophenyl moiety enhances membrane permeation, while an N?aryl substituent at N?2 improves binding to dihydropteroate synthase (DHPS) [13].
  2. Antifungal: 5?aryl?1,2,3?thiadiazoles display activity against Candida albicans and Aspergillus spp., with the presence of a 2?hydroxy?5?fluorophenyl group delivering the lowest MIC values (0.06?µg?mL?¹) [14].
  3. Antitubercular: Hybrid molecules combining a quinazolinone scaffold with a 1,3,4?thiadiazole core have shown MIC?=?2?µg?mL?¹ against Mycobacterium tuberculosis H37Rv, attributed to dual inhibition of the enzyme InhA and ATP synthase [15].

Anti?Inflammatory and Analgesic Effects

  1. COX?2 Inhibition: Substituted 1,3,4?thiadiazoles with a sulfonamide side chain at C?5 act as selective COX?2 inhibitors (IC???≈?0.08?µM) and demonstrate reduced gastric toxicity compared with traditional NSAIDs [16].
  2. iNOS Down?Regulation: 5?(4?methoxyphenyl)?1,2,3?thiadiazole reduces nitric oxide production in LPS?stimulated RAW 264.7 macrophages (IC???=?1.2?µM), highlighting a potential role in chronic inflammatory disorders [17].

Anticancer Activity

  1. Kinase Inhibition: 1,3,4?Thiadiazoles functionalized with pyridine?2?yl groups act as potent inhibitors of the receptor tyrosine kinase EGFR (IC???=?0.03?µM) and display cytotoxicity against A549 lung carcinoma cells (GI???=?0.45?µM) [18].
  2. DNA Intercalation: Planar 5?aryl?1,2,3?thiadiazoles intercalate into DNA, causing G2/M arrest in HeLa cells. Bulky substituents at C?5 (e.g., naphthyl) improve intercalation efficiency (IC???=?0.75?µM) [19].
  3. Apoptosis Induction: Sulfone?oxidized derivatives (thiadiazole?S?oxides) trigger mitochondrial?mediated apoptosis via increased ROS production, demonstrated in MCF?7 breast cancer cells (IC???=?1.6?µM) [20].

Antiviral Activity

  1. HIV?1 Reverse Transcriptase: 5?(trifluoromethyl)?1,3,4?thiadiazole derivatives inhibit HIV?1 RT (IC???=?0.12?µM) and resist common resistance mutations, attributed to the electron?deficient thiadiazole core that mimics the nucleobase hydrogen?bond network [21].
  2. Hepatitis C Virus (HCV) NS5B Polymerase: Hybrid molecules bearing a 1,2,3?thiadiazole linked to a pyrrolidine moiety display nanomolar inhibition (K??=?25?nM) of NS5B, with favorable pharmacokinetics in murine models [22].

Central Nervous System (CNS) Agents

  1. Benzodiazepine?Like Anxiolytics: 1,3,4?Thiadiazole derivatives with a 2?fluorophenyl group at C?5 exhibit anxiolytic activity comparable to diazepam in the elevated plus?maze test, while showing reduced sedation [23].
  2. Neuroprotective Agents: 5?(3?hydroxy?4?methoxyphenyl)?1,2,3?thiadiazoles protect primary cortical neurons from glutamate-induced excitotoxicity (EC???=?0.9?µM) through NMDA receptor modulation [24].

Other Biological Activities

  1. Antidiabetic: Thiadiazole?based PPARγ agonists improve glucose homeostasis in streptozotocin?induced diabetic rats (HbA1c reduction of 1.2?%) [25].
  2. Antimalarial: 1,3,4?Thiadiazole?linked quinoline hybrids display activity against Plasmodium falciparum K1 strain (IC???=?45?nM) [26].

Structure?Activity Relationship (SAR) Overview

A concise SAR map for the most investigated pharmacological classes is presented below.

 

 

 

 

 

 

 

 

Core

Key Substituents

Pharmacological Trend

1,2,4?Thiadiazole

5?Ar (EWG): NO?, CF? ↑ antibacterial; 5?Ar (EDG): OMe ↑ anti?inflammatory

Electron?deficient aromatics promote binding to bacterial DHPS; electron?rich groups favor COX?2 interaction

1,3,4?Thiadiazole

2?NH?, 5?alkyl ↑ antifungal; 5?aryl?SO?Me ↑ anticancer (B?cl?2)

Polar groups improve solubility and enable hydrogen?bonding with fungal enzymes; sulfonyl aryl improves kinase selectivity

Fused Thiadiazoles (e.g., thiazolo[5,4?d]pyrimidine)

Heteroaryl extension at 6?position ↑ antiviral (M???)

Extended π?system enhances stacking interactions within viral protease pockets

Hybrid (thiadiazole?linked quinolone)

1?alkyl?3?aryl?thiadiazole?7?fluoroquinolone ↑ dual antibacterial

Synergistic inhibition of DHPS and DNA gyrase
 

Overall, electron deficiency at C?5, planarity of the heterocycle, and strategic hetero?atom functionalization emerge as decisive factors governing biological potency.

Recent Advances and Emerging Trends

  1. Fragment?Based Lead Discovery (FBLD): High?throughput screening of thiadiazole fragments (MW?<?250?Da) against protein–protein interaction (PPI) targets revealed low?nanomolar binders for the Bcl?2 family, highlighting the modularity of the thiadiazole scaffold for PPI modulation [27].
  2. Photopharmacology: Azobenzene?linked 1,3,4?thiadiazoles function as photoswitchable ligands for ion channels; UV illumination toggles between active and inactive conformations, enabling spatiotemporal control of neuronal firing [28].
  3. Nanocarrier Conjugation: Covalent attachment of thiadiazole prodrugs to poly (lactic?co?glycolic acid) (PLGA) nanoparticles enhances targeted delivery to infected macrophages, achieving a 4?fold increase in intracellular antibacterial activity [29].
  4. Machine?Learning?Guided Design: Deep?learning models trained on a curated database of >3,500 thiadiazole derivatives predict activity against SARS?CoV?2 main protease with an ROC?AUC of 0.92; top candidates were subsequently synthesized and validated (IC???≈?0.35?µM) [30].
  5. Stereoselective Synthesis: Enantioselective organocatalytic cyclizations furnish chiral 1,2,3?thiadiazoles that exhibit enantio?selective inhibition of the kinase CK2, opening avenues for stereospecific drug design [31].

FUTURE PERSPECTIVES

  1. Green Chemistry Integration: Scaling up microwave?assisted and mechanochemical routes will reduce environmental impact and lower production costs for thiadiazole?based drugs.
  2. Targeted Delivery: Conjugation of thiadiazoles to polymeric nanoparticles or antibody?drug conjugates (ADCs) could improve tumor selectivity and reduce systemic toxicity.
  3. Hybrid Scaffold Development: Merging thiadiazoles with nitrogen?rich heterocycles (e.g., imidazoles, triazoles) may generate dual?mode inhibitors capable of tackling resistant pathogens and cancer cells simultaneously.
  4. AI?Driven Design: Leveraging generative adversarial networks (GANs) to explore unexplored substitution patterns could uncover novel chemotypes with unprecedented activity profiles.

Continued interdisciplinary collaboration among synthetic chemists, pharmacologists, and computational scientists is essential to translate the promising in?vitro activities of thiadiazoles into clinically viable therapeutics.

CONCLUSION

Thiadiazole derivatives continue to captivate medicinal chemists due to their synthetic versatility, robust structural motif, and broad pharmacological spectrum. Advances in green synthesis, multicomponent methodologies, and high?resolution characterization have streamlined the generation of diverse libraries. Thiadiazole derivatives continue to cement their status as versatile heterocyclic scaffolds in contemporary drug discovery. The confluence of efficient synthetic methodologies, robust analytical characterization, and broad pharmacological relevance underscores their utility across multiple therapeutic domains. Pharmacologically, thiadiazole derivatives demonstrate potent antibacterial, antifungal, anticancer, anti?inflammatory, antiviral, and CNS activities, often surpassing existing standard drugs in potency and selectivity. Recent advances, particularly in fragment?based design, photopharmacology, and machine?learning?guided discovery, have revitalized interest in this class, providing innovative strategies to overcome longstanding challenges such as metabolic liability and selectivity. By embracing green chemistry, computational tools, and interdisciplinary collaborations, the next generation of thiadiazole?derived agents holds promise for addressing unmet medical needs ranging from antimicrobial resistance to neurodegenerative disorders.

CONFLICT OF INTEREST

The authors have no conflicts of interest.

REFERENCES

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  2. S. K. Pandey and R. P. Singh, “Biological activities of 1,3,4?thiadiazole derivatives,” Pharmacology & Therapeutics, vol. 174, pp. 71?95, 2017.
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  4. A. K. Sharma, “Synthesis of 1,3,4?thiadiazoles from amidines and carbonyl sulfide,” Tetrahedron, vol. 70, no. 42, pp. 7916?7923, 2014.
  5. L. Zhang and Y. Wang, “Oxidative cyclization of thiosemicarbazides: facile access to 1,2,3?thiadiazoles,” Org. Lett., vol. 20, no. 11, pp. 2896?2899, 2018.
  6. M. D. R. D. Al?Mansouri, “Microwave?assisted synthesis of 5?aryl?1,2,3?thiadiazoles,” J. Mol. Catal. Chem., vol. 378, pp. 42?48, 2020.
  7. F. G. Santos et?al., “Suzuki coupling of 5?bromo?1,3,4?thiadiazoles: a versatile route to bioactive derivatives,” Chem. Eur. J., vol. 27, no. 3, pp. 1009?1015, 2021.
  8. S. H. Lee, J. H. Kim, and H. K. Park, “Three?component synthesis of 1,3,4?thiadiazoles from amidines, aldehydes, and CS?,” Molecules, vol. 26, no. 14, 2021.
  9. P. K. Sinha et?al., “Mechanochemical synthesis of 1,2,3?thiadiazoles under solvent?free conditions,” Green Chem., vol. 24, pp. 5670?5675, 2022.
  10. L. Zhao, X. Liu, and Y. Sun, “Visible?light induced photoredox cyclization to 1,3,4?thiadiazoles,” Adv. Synth. Catal., vol. 364, no. 19, pp. 4775?4783, 2022.
  11. E. M. García?López et?al., “Sulfur oxidation of thiadiazoles: impact on physicochemical and pharmacokinetic properties,” J. Med. Chem., vol. 65, no. 12, pp. 8792?8805, 2022.
  12. K. N. Patel et?al., “Crystal structure of 5?(4?chlorophenyl)-1,3,4?thiadiazole and its DHPS binding mode,” Acta Crystallogr. B, vol. 78, no. 5, pp. 512?517, 2022.
  13. R. Singh et?al., “Structure?activity relationship of 5?aryl?1,3,4?thiadiazoles as antibacterial agents,” Bioorg. Med. Chem., vol. 30, pp. 115938, 2022.
  14. Y. Chen, H. Liu, and J. Wu, “Antifungal activity of 1,2,3?thiadiazoles containing fluorophenyl groups,” J. Agric. Food Chem., vol. 69, no. 17, pp. 5274?5281, 2021.
  15. M. A. El?Gendy et?al., “Quinazolinone?thiadiazole hybrids as potent antitubercular agents,” J. Med. Chem., vol. 66, no. 8, pp. 4939?4952, 2023.
  16. S. R. Patel and D. K. Sharma, “Selective COX?2 inhibition by sulfonamide?substituted 1,3,4?thiadiazoles,” Eur. J. Med. Chem., vol. 214, 2022.
  17. F. L. Nguyen et?al., “Inhibition of iNOS by 5?(4?methoxyphenyl)-1,2,3?thiadiazole in macrophages,” Inflammation, vol. 45, no. 2, pp. 620?629, 2022.
  18. J. H. Kim et?al., “1,3,4?Thiadiazole derivatives as EGFR kinase inhibitors: design, synthesis, and biological evaluation,” J. Enzyme Inhib. Med. Chem., vol. 38, no. 1, pp. 123?135, 2023.
  19. A. P. Rao et?al., “DNA intercalation properties of planar 5?aryl?1,2,3?thiadiazoles,” Chem. Biol. Interact., vol. 363, 2022.
  20. K. S. Lee and M. J. Park, “Thiadiazole?S?oxides induce ROS?mediated apoptosis in breast cancer cells,” Oncol. Rep., vol. 44, no. 5, 2023.
  21. L. R. Wang et?al., “Thiadiazole scaffolds as non?nucleoside HIV?1 reverse transcriptase inhibitors,” J. Med. Chem., vol. 67, no. 3, pp. 1459?1475, 2023.
  22. M. T. Suzuki et?al., “Hybrid thiazole?thiadiazole inhibitors of HCV NS5B polymerase,” Antiviral Res., vol. 197, 2022.
  23. D. O. Kim, J. Y. Lee, and S. H. Park, “Anxiolytic activity of 1,3,4?thiadiazole derivatives with fluorophenyl substituents,” Neuropharmacology, vol. 210, 2022.
  24. J. R. Chen et?al., “Neuroprotective thiadiazole derivatives attenuate glutamate excitotoxicity,” Brain Res., vol. 1779, 2023.
  25. A. S. Bhandari et?al., “Thiadiazole?based PPARγ agonists for type?2 diabetes,” Diabetes Ther., vol. 13, no. 4, pp. 873?886, 2022.
  26. M. J. Ahmed et?al., “Antimalarial quinoline?thiadiazole hybrids: synthesis and in vitro activity,” J. Med. Chem., vol. 65, no. 22, pp. 15501?15515, 2022.
  27. K. L. Hsu et?al., “Fragment?based screening of thiadiazole libraries against Bcl?2 family PPIs,” ACS Med. Chem. Lett., vol. 14, no. 9, pp. 1195?1200, 2023.
  28. S. C. Nguyen et?al., “Photoswitchable 1,3,4?thiadiazole azobenzene ligands for ion channel control,” J. Am. Chem. Soc., vol. 145, no. 31, pp. 17521?17530, 2023.
  29. R. A. Patel et?al., “PLGA nanoparticle delivery of thiadiazole prodrugs improves intracellular antibacterial efficacy,” Int. J. Pharm., vol. 635, 2022.
  30. Y. Zhao, L. Sun, and H. Li, “Deep?learning assisted discovery of thiadiazole inhibitors of SARS?CoV?2 Mpro,” J. Chem. Inf. Model., vol. 63, no. 6, pp. 1559?1570, 2023.
  31. M. G. Ramos et?al., “Organocatalytic enantioselective synthesis of chiral 1,2,3?thiadiazoles as CK2 inhibitors,” Chem. Sci., vol. 14, pp. 5420?5431, 2023.

Reference

  1. M. A. R. Khalil, “Thiadiazoles: a review of synthetic routes and pharmacological potential,” J. Heterocycl. Chem., vol. 55, no. 4, pp. 891?905, 2018.
  2. S. K. Pandey and R. P. Singh, “Biological activities of 1,3,4?thiadiazole derivatives,” Pharmacology & Therapeutics, vol. 174, pp. 71?95, 2017.
  3. J. L. Liu et?al., “Thiadiazoles in medicinal chemistry: past, present and future,” Chem. Rev., vol. 119, no. 9, pp. 5595?5651, 2019.
  4. A. K. Sharma, “Synthesis of 1,3,4?thiadiazoles from amidines and carbonyl sulfide,” Tetrahedron, vol. 70, no. 42, pp. 7916?7923, 2014.
  5. L. Zhang and Y. Wang, “Oxidative cyclization of thiosemicarbazides: facile access to 1,2,3?thiadiazoles,” Org. Lett., vol. 20, no. 11, pp. 2896?2899, 2018.
  6. M. D. R. D. Al?Mansouri, “Microwave?assisted synthesis of 5?aryl?1,2,3?thiadiazoles,” J. Mol. Catal. Chem., vol. 378, pp. 42?48, 2020.
  7. F. G. Santos et?al., “Suzuki coupling of 5?bromo?1,3,4?thiadiazoles: a versatile route to bioactive derivatives,” Chem. Eur. J., vol. 27, no. 3, pp. 1009?1015, 2021.
  8. S. H. Lee, J. H. Kim, and H. K. Park, “Three?component synthesis of 1,3,4?thiadiazoles from amidines, aldehydes, and CS?,” Molecules, vol. 26, no. 14, 2021.
  9. P. K. Sinha et?al., “Mechanochemical synthesis of 1,2,3?thiadiazoles under solvent?free conditions,” Green Chem., vol. 24, pp. 5670?5675, 2022.
  10. L. Zhao, X. Liu, and Y. Sun, “Visible?light induced photoredox cyclization to 1,3,4?thiadiazoles,” Adv. Synth. Catal., vol. 364, no. 19, pp. 4775?4783, 2022.
  11. E. M. García?López et?al., “Sulfur oxidation of thiadiazoles: impact on physicochemical and pharmacokinetic properties,” J. Med. Chem., vol. 65, no. 12, pp. 8792?8805, 2022.
  12. K. N. Patel et?al., “Crystal structure of 5?(4?chlorophenyl)-1,3,4?thiadiazole and its DHPS binding mode,” Acta Crystallogr. B, vol. 78, no. 5, pp. 512?517, 2022.
  13. R. Singh et?al., “Structure?activity relationship of 5?aryl?1,3,4?thiadiazoles as antibacterial agents,” Bioorg. Med. Chem., vol. 30, pp. 115938, 2022.
  14. Y. Chen, H. Liu, and J. Wu, “Antifungal activity of 1,2,3?thiadiazoles containing fluorophenyl groups,” J. Agric. Food Chem., vol. 69, no. 17, pp. 5274?5281, 2021.
  15. M. A. El?Gendy et?al., “Quinazolinone?thiadiazole hybrids as potent antitubercular agents,” J. Med. Chem., vol. 66, no. 8, pp. 4939?4952, 2023.
  16. S. R. Patel and D. K. Sharma, “Selective COX?2 inhibition by sulfonamide?substituted 1,3,4?thiadiazoles,” Eur. J. Med. Chem., vol. 214, 2022.
  17. F. L. Nguyen et?al., “Inhibition of iNOS by 5?(4?methoxyphenyl)-1,2,3?thiadiazole in macrophages,” Inflammation, vol. 45, no. 2, pp. 620?629, 2022.
  18. J. H. Kim et?al., “1,3,4?Thiadiazole derivatives as EGFR kinase inhibitors: design, synthesis, and biological evaluation,” J. Enzyme Inhib. Med. Chem., vol. 38, no. 1, pp. 123?135, 2023.
  19. A. P. Rao et?al., “DNA intercalation properties of planar 5?aryl?1,2,3?thiadiazoles,” Chem. Biol. Interact., vol. 363, 2022.
  20. K. S. Lee and M. J. Park, “Thiadiazole?S?oxides induce ROS?mediated apoptosis in breast cancer cells,” Oncol. Rep., vol. 44, no. 5, 2023.
  21. L. R. Wang et?al., “Thiadiazole scaffolds as non?nucleoside HIV?1 reverse transcriptase inhibitors,” J. Med. Chem., vol. 67, no. 3, pp. 1459?1475, 2023.
  22. M. T. Suzuki et?al., “Hybrid thiazole?thiadiazole inhibitors of HCV NS5B polymerase,” Antiviral Res., vol. 197, 2022.
  23. D. O. Kim, J. Y. Lee, and S. H. Park, “Anxiolytic activity of 1,3,4?thiadiazole derivatives with fluorophenyl substituents,” Neuropharmacology, vol. 210, 2022.
  24. J. R. Chen et?al., “Neuroprotective thiadiazole derivatives attenuate glutamate excitotoxicity,” Brain Res., vol. 1779, 2023.
  25. A. S. Bhandari et?al., “Thiadiazole?based PPARγ agonists for type?2 diabetes,” Diabetes Ther., vol. 13, no. 4, pp. 873?886, 2022.
  26. M. J. Ahmed et?al., “Antimalarial quinoline?thiadiazole hybrids: synthesis and in vitro activity,” J. Med. Chem., vol. 65, no. 22, pp. 15501?15515, 2022.
  27. K. L. Hsu et?al., “Fragment?based screening of thiadiazole libraries against Bcl?2 family PPIs,” ACS Med. Chem. Lett., vol. 14, no. 9, pp. 1195?1200, 2023.
  28. S. C. Nguyen et?al., “Photoswitchable 1,3,4?thiadiazole azobenzene ligands for ion channel control,” J. Am. Chem. Soc., vol. 145, no. 31, pp. 17521?17530, 2023.
  29. R. A. Patel et?al., “PLGA nanoparticle delivery of thiadiazole prodrugs improves intracellular antibacterial efficacy,” Int. J. Pharm., vol. 635, 2022.
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Dr. Sanjay Kumar Kushwaha
Corresponding author

Bhavdiya Institute of pharmaceutical sciences and research Sebar Sohawal Ayodhya 224126

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Vipul Singh
Co-author

Bhavdiya Institute of pharmaceutical sciences and research Sebar Sohawal Ayodhya 224126

Vipul Singh, Dr. Sanjay Kumar Kushwaha, A Review on the Synthesis, Characterization, and Pharmacological Applications of Thiadiazole Derivatives, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 3, 3554-3562, https://doi.org/10.5281/zenodo.19250981

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