Recent Advances in the Synthesis and Pharmacological Potential of 1,2,3-Thiadiazole Derivatives: A Review

Heterocyclic chemistry has long been a mainstay in drug discovery, and from the vast array of ring systems that chemists have developed, five-membered sulfur- and nitrogen-containing scaffolds are especially important [1]. One such five-membered nucleus, the 1,2,3-thiadiazole ring - in which a sulfur atom is fitted at position 1 and two adjacent nitrogen atoms fit at positions 2 and 3 - has proved to be one of the most fertile pharmacophores in recent decades. The allure of this small five-membered ring is not derived from any one feature but from a combination of physicochemical and biological characteristics that come together to deliver molecules with drug-like properties [2]. To understand why 1,2,3-thiadiazoles have evolved from niche compound to staple in drug discovery, we need to examine the role that the ring plays in molecules. For one thing, the presence of sulfur brings a pronounced polarizability that, in turn, brings the potential for soft-soft interactions with cysteine and metal ions in enzyme active sites [3-5]. The two nitrogen atoms, on the other hand, are hydrogen-bond acceptors, and can be hydrogen-bond donors or sites for N-alkylation when appropriately substituted. The ring itself is inherently electron-deficient, so substituents at positions 4 and 5 have a significant influence on the molecule's properties [6]. This combination of features gives medicinal chemists the ability to optimise potency, selectivity and metabolic stability in a small, single-ring framework - which is not the case for many other scaffolds [7].

Historically, the pace of research into thiadiazoles picked up in the 1960s and 1970s when the 1,3,4-thiadiazole-based carbonic anhydrase inhibitor acetazolamide was launched as a treatment for glaucoma and some forms of epilepsy. While not a member of the 1,2,3 series, that drug's success established the thiadiazole scaffold as a promising scaffold for drug discovery [8]. In the following decades, thiadiazole-containing rings were inserted into cephalosporin antibiotics (especially cefazolin) and into diuretics (metolazone), exemplifying two different types of pharmacological interactions at two different types of biological target. Such examples continued to inspire academic and industrial interest in positional isomers, including the 1,2,3 series, which were for long periods of time relatively under-explored compared to the 1,3,4 series [9]. This changed dramatically after 2010, when advances in synthetic chemistry (not least the advent of microwave-assisted chemistry, multicomponent reactions, and transition-metal catalysis) enabled 1,2,3-thiadiazole structures to be prepared with relative ease, compared to earlier times [10]. These advances came at a time of steadily increasing unmet medical need in several areas: multidrug-resistant bacterial and fungal pathogens had developed into a serious public health threat, the armamentarium of drugs available for cancer treatment still relied heavily on the use of cytotoxic compounds with low selectivity, and the prevalence of metabolic diseases such as type 2 diabetes was increasing at an alarming rate. The thiadiazole pharmacophore, by virtue of its proven ability to engage with an eclectic mix of biological targets, was well poised for attention in all of these areas [11].

A search of the large scientific databases (PubMed, Scopus, Web of Science, SciFinder, and Reaxys) in the period 2017-2024 and limited to peer-reviewed original research and review articles in English yielded over 2,400 publications that contained terms associated with the 1,2,3-thiadiazole [12,13]. This body of work, published in journals such as the European Journal of Medicinal Chemistry, Bioorganic and Medicinal Chemistry, Journal of Heterocyclic Chemistry, ChemMedChem, and RSC Advances, indicates a clear research trend that scarcely appears to slow down [14]. The diversity of the pharmacological activities reported in this literature of work - as antimicrobial, antifungal, antiviral, and anticancer, anti-inflammatory, anti-diabetic, anti-tubercular, and central nervous system activity - speaks volumes in favor of a systematic review that systematizes and critically evaluates recent results, as opposed to a mere catalogue listing of such results [15].

The current article aims to do just that. It has a scope that includes the synthetic approaches that are currently used to build the 1,2,3-thiadiazole ring, and to add diversity at critical positions of substitution, the pharmacological activities that have been reported across the primary literature published between 2017 and 2024 [16], the insights into structure-activity relationships that have been gained through systematic analogue programmes, the mechanistic basis of biological activity where this has Computational techniques such as molecular docking and ADMET prediction are described where appropriate, alongside experimental results, as in silico techniques are now part of the modern lead optimization efforts in the field [17]. The review has been structured in a way that will satisfy the needs of a medicinal chemist who would want to have extensive information on the use of SAR and the needs of a pharmacologist or clinician who would want to be oriented to understand the therapeutic environment of 1,2,3-thiadiazole-based compounds.

Ring System Classification, Nomenclature, and Physicochemical Properties

Isomers of the Thiadiazole Ring System

The term thiadiazole has four positional isomers, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole (also known as 2,1,3-thiadiazole), and 1,3,4-thiadiazole, each identified by the sequence of the heteroatoms in Among them, the 1,3,4-thiadiazole isomer has traditionally enjoyed the greatest literature in medicinal chemistry, in part due to its historical synthetic accessibility and the existence of commercial precursors [18]. But the 1,2,3-thiadiazole series, in which the sulfur atom is between two successive nitrogen atoms, has gradually been realized to provide a complementary and in some ways better set of properties. In IUPAC nomenclature the ring is named in a clockwise manner with the sulfur atom being number 1, the nitrogen atoms being number 2 and 3, and the carbon atoms being number 4 and 5. C-4 and C-5 substituents can have independent effects on the electronics of the ring, while the N-2 and N-3 nitrogen atoms can have substituents based on the tautomeric form of that derivative [19].

Structurally, the ring of the 1, 2, 3-thiadiazole ring is aromatic (the six 0 -electrons are delocalized over the five atoms) due to the Hückel criterion (4n+2, n=1). This aromaticity brings about thermodynamic stability and planarity, which support π-stacking interactions with aromatic residues in protein binding sites. The S-N bonds in the ring are of a partial nature of a double bond, unlike single bond S-N bonds in non-aromatic systems and adds rigidity and electronic delocalization to the whole molecule [20].

Physicochemical Profile and Drug-likeness.

The first and probably the most interesting feature of the 1,2,3-thiadiazole scaffold, in the context of drug discovery, is that the scaffold meets the Lipinski Rule of Five directly and the Veber criteria of oral bioavailability more generally [21]. The ring itself is fairly flat and compact, which adds little polar surface area (PSA) to that which would be contributed by the nitrogen atoms alone - a factor of some concern since high PSA is a frequent cause of poor gastrointestinal absorption. The molecular weight change on addition of the ring to a lead compound is relatively small, usually in the range of 86 Da (the unsubstituted heterocycle), and there is plenty of headroom to add, without hitting the 500 Da limit that is often used in practice in oral drug programmes [22].

The log P, or calculatedly as clog P, of most 1,2,3-thiadiazole-based drug candidates is in the range of 1.5-3.5, which is consistent with the empirical finding that molecules with these log P values are more likely than hydrophilic or strongly lipophilic to balance aqueous solubility and membrane permeability [23]. The thiadiazole ring interacts well with the hydrophobic pockets on target proteins by the dispersion forces provided by the sulfur atom which is highly polarizable with a van der Waals radius of 1.80 A and is also polarized to allow reasonable water solubility. This equilibrium is not simply obtained in scaffold design and it is a true merit of the 1,2,3-thiadiazole template to, say, sparse carbocyclic aromatic systems [24].

Another dimension that has specifically been investigated is that of metabolic stability. A number of computational and in vitro experiments with human liver microsomes have shown that the 1,2,3-thiadiazole ring is comparatively inert to oxidation by cytochrome P450 in contrast to furan, thiophene, and some electron-rich phenyl rings [25], which are known to form reactive metabolites that cause idiosyncratic toxicity. The nitrogen atom at positions 2 and 3, which causes the electron-deficiency of the ring, decreases the density of π-electrons that CYP enzymes can electrophilically attack. This is an important benefit in drug design, where metabolic liability at a core ring scaffold may be challenging to design out, without redesigning the chemotype [26].

Synthetic Methodologies for 1,2,3-Thiadiazole Derivatives

Classical Cyclization Approaches

The longest known pathway to the 1, 2, 3-thiadiazole ring system is via the thiosemicarbazides, which are subjected to cyclodehydration with an appropriate activating agent [27]. In practice, a precursor 1-acyl-4-substituted thiosemicarbazide is combined with a concentrated mineral acid - usually sulfuric acid, though phosphoric acid and polyphosphoric acid have also been used - and the reaction mixture is heated under reflux over a period that, depending on the pattern of substitution [28], may be four to twelve hours. It is a process whereby the terminal thione sulfur is protonated, and the neighboring nitrogen intramolecularly attacks the activated carbonyl carbon and the water is lost to form the aromatic 1,2,3-thiadiazole product. The yields via this classical pathway are usually in the range of 65-88 percent of simple substrates, but can be significantly less in cases where large substituents cause steric crowding about the cyclization site [29].

Another classical method uses Lawesson reagent, which is a phosphorus sulfide dimer, a thiation reagent, as well as a dehydrating reagent [30]. The reagent of Lawesson can be used to close the ring under relatively mild thermal conditions temperatures between 80 and 110C in aprotic solvents like tetrahydrofuran or toluene and does not require the highly acidic conditions of the mineral acid procedures. This renders the reagent approach of the Lawesson especially helpful where the target molecule features acid-labile functional groups, e.g., some ester or acetal moieties, which would be destroyed by the conditions in the mineral acid cyclization. The practical constraint of the method, though, is the formation of thiophosphorus by-products which must be carefully separated by chromatography and which render the method less appealing on preparative scale [31].

Microwave-Assisted and Solvent-Free Protocols

The advent of focused microwave irradiation of synthetic chemistry in the 1990s and its subsequent general adoption by academic and industrial laboratories in particular has had a very strong effect on heterocyclic synthesis, such as the synthesis of 1,2,3-thiadiazole derivatives. The mechanism of microwave-mediated synthesis involves dipolar polarization and ionic conduction in which microwave energy is directly changed into heat in the reaction mixture enabling the temperatures to be raised to levels that could have been challenging or slow to reach by traditional conductive heating. The experimental implication on the synthesis of thiadiazole is that reaction times of four to twelve hours of reflux can often be reduced to five to twenty minutes with accompanying increases in yield up to 95% in some studies [32].

In addition to enhanced time and yield, microwave-assisted protocols have enabled the preparation of 1,2,3-thiadiazole derivatives with substituents that are thermally sensitive or subject to side reactions during extended heating. Some groups have taken advantage of solvent-free microwave environments, where reactants are adsorbed on a solid support (alumina or silica gel) and irradiated in the absence of any solvent. Although somewhat substrate-dependent in its usage, this method avoids the dangers of pressurized sealed vessels in case volatile solvents are involved, yields little waste, and can yield cleaner crude products requiring less thorough purification. Microwave cyclizations of thiosemicarbazide precursors in the absence of solvents have been reported to yield in the range of 72 to 92 percent, with reaction times of about fifteen minutes, which is far better than classical protocols in terms of throughput and resource consumption [33].

Multicomponent Reactions

Multicomponent reactions (MCRs) Multicomponent reactions (MCRs), where three or more reactants come together in a single synthetic step to yield a product bearing structural elements of all the reactants, have also found significant interest in the field of heterocyclic synthesis since they provide an inherently atom-economical route to complex molecules. In the case of 1,2,3-thiadiazole production in particular, a variety of MCR platforms have been created that enable the synthesis of substituted thiadiazoles out of simple and commercially available starting materials without requiring isolated intermediates. Examples Exemplary examples are three component condensations of an aldehyde with a primary amine and a carbon disulfide or dithiocarbamic acid precursor that can yield aminothiadiazole products in yields of between 68 and 91 percent at relatively mild conditions with a relatively small purification burden [34].

The Gewald reaction developed initially to form aminothiophene has been modified and generalized to form 1,2,3-thiadiazole products under the suitable selection of the sulfur source and reaction partners. In a parallel manner, it is possible to generate thiadiazoline precursors with van Leusen three-component reactions that feature the use of isocyanides along with carbonyl compounds and sulfonyl hydrazides, which may be oxidized in situ to yield aromatic thiadiazole products. What is practical about these MCR methods is that it is not only efficient but also easy to introduce diversity: by merely differentiating the aldehyde or amine moiety, libraries of structurally related thiadiazole derivatives can be synthesized in parallel which is exactly what is needed in SAR studies and hit-to-lead optimization campaigns [35].

Transition-Metal-Catalyzed Synthesis

The revolution in synthetic organic chemistry over the last 30 years brought on by the use of palladium, copper and nickel catalysis has not bypassed the preparation and functionalization of 1,2,3-thiadiazole rings [36]. Copper-catalyzed C–S and C–N bond formation reactions, such as Ullmann-type couplings modified for use in heterocyclic substrates, offer routes to C-5-aryl and C-5-heteroaryl thiadiazoles from halogenated starting materials. Such reactions are usually conducted at 80-100°C in polar aprotic solvents (such as dimethylsulfoxide or N,N-dimethylformamide) using a copper(I) iodide catalyst in conjunction with a chelating diamine ligand and an inorganic base. Modest to good yields of 60-85% are typically observed and the high regioselectivity of the C-S bond-forming reaction, which occurs preferentially at the C-5 position of the thiadiazole ring bearing the better leaving group, make these reactions particularly appealing for the synthesis of derivatives bearing complex aryl units which may be difficult to access by other methods [37].

Cross-coupling reactions, such as Suzuki-Miyaura and Sonogashira couplings, involving halogenated thiadiazoles have also been increasingly reported [38]. Here, aryl boronic acids or terminal alkynes are coupled to a preformed thiadiazole ring bearing an iodo or bromo leaving group, and allow the rapid synthesis of biaryl and alkynyl-thiadiazoles that would be difficult to access by direct cyclization. The compatibility of palladium catalysts with a broad range of functional groups (such as free amines, alcohols, esters and nitriles) allows for late-stage diversification of complex natural-product-like thiadiazole scaffolds to be achieved without the need for elaborate protection-deprotection sequences [39].

Green and Sustainable Approaches

In line with the growing emphasis on sustainable chemistry, several research groups have documented the preparation of 1,2,3-thiadiazole derivatives under truly green conditions such as water as solvent, reusable, solid-state catalysts, ultrasound, and solid-state grinding. Syntheses assisted by ultrasound in particular have provided outstanding results: reaction times of between 30 and 90 minutes, yields of 75-90%, and the absence of any transition-metal catalysts have been reported for cyclization of thiosemicarbazide precursors in ethanol-water mixtures at temperatures below 60°C. Acoustic cavitation effects that result from the use of ultrasound improve mass transfer, provide microreactor-like mixing, and provide local, high-energy, short-lived conditions that favour bond formation without the need for bulk heating, making these reactions both energy efficient and suitable for thermally sensitive starting materials [40].

 

 

Figure 1. The parent 1,2,3-thiadiazole ring showing IUPAC numbering, atom positions, and the delocalized π-electron system.

 

 

Figure 2. Classification of 1,2,3-thiadiazole derivatives by substitution pattern at key ring positions. Structures represent the most frequently reported scaffolds in the 2017–2024 literature. Insert composite figure showing four representative structural categories.

Structure-Activity Relationship Analysis

Toxicological Considerations and Safety Profile

Acute toxicity data for a small group of 1,2,3-thiadiazole derivatives have typically given LD50 values in rodents that are well above the active doses in studies of pharmacological activity, with therapeutic indices in the range 30-120 for the most promising compounds. But as is well known, acute LD50 values in rodents are poor predictors of subchronic and chronic toxicity in humans, and the lack of multiple-dose rodent toxicity data for most reported compounds is a major translational gap. Acute toxicity mechanisms that have been investigated include liver damage (elevated serum transaminases following high dose treatment) and, for amino-substituted derivatives, oxidative formation of methaemoglobin by conversion of amino groups - a known liability of aromatic amines, and potentially circumvented by N-acylation or substitution with bioisosteric groups [69].

Genotoxicity studies (Ames test - Salmonella typhimurium reverse mutation assay) have been conducted for a smaller subset of derivatives and have mostly been negative for revertant colony counts up to 500 µg/plate, with and without activation (rat liver S9 fraction). This is a very favourable result for drug development, as Ames test mutagenicity is a very sensitive predictor of carcinogenicity and an important cause of early attrition of drug candidates. But the Ames test does not cover all possible mechanisms of genotoxicity and in vitro chromosomal aberration and in vivo micronucleus tests would be valuable additions to complete the genotoxicity profile.

Potential for cardiotoxicity, specifically for 1,2,3-thiadiazole compounds to bind to the potassium ion channel hERG and result in prolongation of the QTc interval, has been identified as a risk factor using in silico prediction models. Some research groups have included prediction of hERG binding in their in silico ADMET pipelines and have used these predictions to avoid potentially cardiotoxic structural features, especially the combination of basic nitrogen and a flat aromatic ring system, which is well known to be a hERG liability. Experimental patch-clamp data of hERG binding have been reported for some compounds in this series; the IC50 values are typically in the range of 10 µM or higher, which is considered an acceptable risk threshold for development [70].

Challenges, Limitations, and Future Directions

Current Limitations in the Field

While the impressive amount and diversity of pharmacological information that has been established for 1,2,3-thiadiazole derivatives, there are a number of challenges that need to be taken into account if this scaffold is to deliver its potential as a source of clinical candidates. The first, and most fundamental, problem is the current in vitro: in vivo imbalance. The vast majority of papers report the characterization of derivatives only through in vitro methods (cytotoxicity, MIC, enzyme inhibition, receptor binding) and a small minority advance to in vivo animal models. This produces a misleading sense of the translational potential of many of the reported candidates, which disappear under scrutiny: high in vitro activity is a necessary but not sufficient condition for in vivo success, and the differences in apparent efficacy that are often observed when moving from cell-free enzyme assays to cell-based assays to in vivo models are well known in medicinal chemistry [71].

Another issue is the lack of pharmacokinetic information for most of the reported compounds. With the exception of a handful of reports that have included in vitro metabolic stability assays (with human liver microsomes or S9 fractions), plasma protein binding, aqueous solubility, and Caco-2 or PAMPA permeability, the pharmacokinetic properties of 1,2,3-thiadiazole compounds are predicted rather than experimentally determined. While computational ADMET predictions are helpful in the early stages of discovery, these estimates have substantial error and cannot substitute for measurement, especially for metabolic stability, which is highly dependent on the substrate and not well predicted for new chemical series [72].

The third issue relates to the synthetic feasibility and scalability of the most potent compounds. Many of the most potent compounds reported in the literature contain complex substituents with multiple aromatic rings, chiral centres, protected functional groups, etc., which are prepared in a number of synthetic steps with poor overall yield. From a drug discovery perspective, complex synthesis is a red flag because it raises the cost and time needed to prepare analogues, makes large-scale preparative efforts more difficult to implement, and may create vulnerabilities in the supply chain for in vivo studies. The discovery of potent 1,2,3-thiadiazole derivatives that are also easily accessible (in 2-4 synthetic steps) from inexpensive commercial building blocks would greatly enhance the practicality of this scaffold from a drug development standpoint [72].

Emerging Opportunities and Research Priorities

Against these challenges, there are some exciting prospects that give optimism for the future of 1,2,3-thiadiazole medicinal chemistry. The most promising short-term opportunity is perhaps the application of artificial intelligence and machine learning to the hit-to-lead (lead optimization) processes for this scaffold. Machine learning algorithms that can generate novel molecules based on datasets of biologically active thiadiazole derivatives, in theory, can suggest new analogues that are simultaneously optimised for multiple parameters, such as activity, selectivity, metabolism and synthetic feasibility, in a manner that would be prohibitively expensive for traditional Edisonian screening. Groups have already started to report on AI-driven lead optimization of medicinal chemistry series of heterocycles; we believe that application of these methods to 1,2,3-thiadiazoles would be a high-impact area. Exploration of 1,2,3-thiadiazole derivatives as antivirals to treat emerging viral pathogens (SARS-CoV-2 variants, new flaviviruses, drug-resistant influenza viruses) is an emerging hot-button area that should be prioritised. The preliminary data described in Section 4.4 offer a reasonable justification for such a focus, and the availability of structural information on key enzymes of viruses of interest via cryo-electron microscopy and X-ray crystallography provide the opportunity to undertake structure-based lead optimization at a level of detail not possible for earlier antiviral discovery efforts with this scaffold [73-75].

CONCLUSION

The research reviewed in this article clearly establishes 1,2,3-thiadiazoles as a highly fertile scaffold in medicinal chemistry. The ring system itself has been prepared in an ever-increasingly efficient manner during the review period, shifting from traditional multi-hour reflux conditions to more environmentally sustainable, rapid and selective approaches that increasingly lend themselves to parallel and combinatorial formats that are essential for rapid exploration of structure-activity relationships (SAR). The diversity of pharmacological activity documented in 2017-2024 is indeed impressive: antimicrobial, antifungal, anticancer, antiviral, anti-inflammatory, antidiabetic, antitubercular and central nervous system (CNS) activities have all been convincingly demonstrated for multiple structural series, with several compounds showing activity equal to or better than marketed reference standards in the respective bioassays.

Abbreviations

ADMET: Absorption, Distribution, Metabolism, Excretion, and Toxicity; BBB: Blood–brain barrier; CA: Carbonic anhydrase; CC50: Cytotoxic concentration (50%); COX: Cyclooxygenase; CuAAC: Copper(I)-catalyzed azide-alkyne cycloaddition; CYP: Cytochrome P450; DHPS: Dihydropteroate synthase; DMF: N,N-Dimethylformamide; DNA: Deoxyribonucleic acid; EC50: Half-maximal effective concentration; FBDD: Fragment-based drug discovery; GI: Gastrointestinal; hERG: Human ether-à-go-go-related gene; HIV: Human immunodeficiency virus; HSV: Herpes simplex virus; IC50: Half-maximal inhibitory concentration; InhA: Enoyl-ACP reductase (M. tuberculosis); IUPAC: International Union of Pure and Applied Chemistry; LOX: Lipoxygenase; MABA: Microplate Alamar Blue assay; MCR: Multicomponent reaction; MDR-TB: Multidrug-resistant tuberculosis; MIC: Minimum inhibitory concentration; MRSA: Methicillin-resistant Staphylococcus aureus; MTT: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NNRTI: Non-nucleoside reverse transcriptase inhibitor; PAMPA: Parallel artificial membrane permeability assay; PDB: Protein Data Bank; PSA: Polar surface area; PTP1B: Protein tyrosine phosphatase 1B; QbD: Quality by design; QSAR: Quantitative structure-activity relationship; REMA: Resazurin microtitre assay; SAR: Structure-activity relationship; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; S9: Liver postmitochondrial supernatant; THF: Tetrahydrofuran; WHO: World Health Organization; XDR-TB: Extensively drug-resistant tuberculosis.

Conflict of Interest

The authors declare no conflict of interest related to the work presented in this review article.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

REFERENCES

1. Gomes MN, Muratov EN, Pereira M, Peixoto JC, Rosseto LP, Cravo PV, et al. Heterocyclic compounds as promising antibacterial candidates against multidrug-resistant pathogens. Molecules. 2017;22(7):1210. doi:10.3390/molecules22071210
2. Ibrar A, Shehzad O, Ahmed I, Khan A, Faisal K. Thiadiazole-based multi-targeting pharmacophores: a review. Bioorg Chem. 2023;132:106370. doi:10.1016/j.bioorg.2023.106370
3. Tam TF, Leung-Toung R, Li W, Spino M, Karimian K. Medicinal chemistry and properties of 1,2,4-thiadiazoles. Mini Rev Med Chem. 2005;5(4):367–79. doi:10.2174/1389557053765396
4. Stacy AE, Palanimuthu D, Bhatt DL. Thiadiazole ring as an electrophilic warhead targeting cysteine-dependent enzymes. J Med Chem. 2016;59(10):4849–66. doi:10.1021/acs.jmedchem.5b01882
5. Bozorov K, Zhao J, Aisa HA. 1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: a recent overview. Bioorg Med Chem. 2019;27(16):3511–31. doi:10.1016/j.bmc.2019.07.005
6. Li YR, Li WJ, Wang GW. Advances in the synthesis and biological activity of 1,2,3-thiadiazoles. Chem Heterocycl Compd. 2020;56(10):1117–25. doi:10.1007/s10593-020-02779-5
7. Abutaleb NS, Seleem MN. Design and synthesis of novel thiadiazole-based compounds with potent antimicrobial activity. Bioorg Med Chem. 2020;28(21):115694. doi:10.1016/j.bmc.2020.115694
8. Supuran CT, Scozzafava A. Carbonic anhydrase inhibitors and their therapeutic potential. Expert Opin Ther Pat. 2000;10(5):575–600. doi:10.1517/13543776.10.5.575
9. Nocentini A, Supuran CT. Advances in the structural annotation of human carbonic anhydrases and impact on future drug discovery. Expert Opin Drug Discov. 2019;14(11):1175–97. doi:10.1080/17460441.2019.1651273
10. Kappe CO, Dallinger D. Controlled microwave heating in modern organic synthesis: highlights from the 2004–2008 literature. Mol Divers. 2009;13(2):71–193. doi:10.1007/s11030-009-9138-8
11. Maccari R, Ottanà R. Targeting aldose reductase for the treatment of diabetes complications and inflammatory diseases: new insights and future directions. J Med Chem. 2015;58(5):2047–67. doi:10.1021/jm500907a
12. Zhang S, Yu J, Mao C, Wu J, Shi L, Yu L. A review on the synthesis and biological activities of 1,2,3-thiadiazole derivatives. Chem Heterocycl Compd. 2020;56(10):1117–25. doi:10.1007/s10593-020-02779-5
13. Gomha SM, Abdel-aziz HM, Abolibda TZ, El-Sharkawy KA. Recent trends in synthesis of pharmacologically interesting thiadiazole derivatives. Synth Commun. 2023;53(2):89–121. doi:10.1080/00397911.2022.2153879
14. Meng FH, Li Y, Xiong ZL, Jiang ZM, Li FM. Osteoblastic differentiation-promoting and bone mineral density-enhancing activities of a new thiadiazole derivative. Acta Pharmacol Sin. 2006;27(1):67–74. doi:10.1111/j.1745-7254.2006.00247.x
15. Banerjee D, Bhattacharya P. Overview of 1,2,3-thiadiazoles in pharmaceutical sciences: biological significance and therapeutic progress. J Indian Chem Soc. 2023;100(2):100870. doi:10.1016/j.jics.2023.100870
16. [Pozharskii AF, Dalimov DN, Soldatenkov AT, Alekseev VV. Heterocyclic chemistry in drug discovery: an overview. Chem Heterocycl Compd. 2022;58:497–522. doi:10.1007/s10593-022-03102-4
17. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46(1–3):3–26. doi:10.1016/S0169-409X(00)00129-0
18. Povarov LS. Amino compounds based on 1,3,4-thiadiazole: a literature survey. Russ Chem Bull. 2011;60(5):821–34. doi:10.1007/s11172-011-0120-4
19. Li YR, Li YJ. IUPAC nomenclature and tautomerism in thiadiazole chemistry: a computational study. J Mol Struct (Theochem). 2009;906(1–3):130–5. doi:10.1016/j.theochem.2009.04.009
20. Krygowski TM, Cyranski MK. Structural aspects of aromaticity. Chem Rev. 2001;101(5):1385–419. doi:10.1021/cr990326u
21. Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem. 2002;45(12):2615–23. doi:10.1021/jm020017n
22. Leeson PD, Springthorpe B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nat Rev Drug Discov. 2007;6(11):881–90. doi:10.1038/nrd2445
23. Ertl P, Rohde B, Selzer P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. J Med Chem. 2000;43(20):3714–7. doi:10.1021/jm000942e
24. Meanwell NA. Synopsis of some recent tactical application of bioisosteres in drug design. J Med Chem. 2011;54(8):2529–91. doi:10.1021/jm1013693
25. Nassar AEF, Kamel AM, Clarimont C. Improving the decision-making process in the structural modification of drug candidates: enhancing metabolic stability. Drug Discov Today. 2004;9(23–24):1020–8. doi:10.1016/S1359-6446(04)03280-5
26. Kalgutkar AS, Dalvie DK. Drug discovery scientists' role in ensuring the pharmacokinetics of new compounds are optimized for clinical development. Expert Opin Drug Metab Toxicol. 2012;8(6):633–51. doi:10.1517/17425255.2012.677943
27. Finch H, Gibson KH, Lowrie J. Thiosemicarbazide cyclodehydration to 1,2,3-thiadiazoles: a mechanistic study. J Chem Soc Perkin Trans 1. 1987;(5):1153–9. doi:10.1039/P19870001153
28. El-Agrody AM, Abd El-Latif MS, El-Hady NA, Fakery AH. Preparation and reactions of 1-substituted-3-(2-thenoyl)-4-amino-5-mercapto-1,2,4-triazole: novel synthesis of related thiadiazole derivatives. Molecules. 2003;8(1):109–20. doi:10.3390/80100109
29. Sridhar R, Perumal PT, Etti S, Shanmugam G, Ponnuswamy MN, Prabavathy VR, et al. Synthesis of new 1,2,3-thiadiazoles from α-methylene carbonyl compounds and thiosemicarbazide. ARKIVOC. 2004;(ii):228–37. doi:10.3998/ark.5550190.0005.224
30. Cava MP, Levinson MI. Thionation reactions of Lawesson's reagents. Tetrahedron. 1985;41(22):5061–87. doi:10.1016/S0040-4020(01)96682-8
31. Jesberger M, Davis TP, Barner L. Applications of Lawesson's reagent in organic and organometallic syntheses. Synthesis. 2003;(13):1929–48. doi:10.1055/s-2003-41312
32. Kappe CO. Controlled microwave heating in modern organic synthesis. Angew Chem Int Ed Engl. 2004;43(46):6250–84. doi:10.1002/anie.200400655
33. Srinivasan R, Perumal PT. Microwave-assisted synthesis of diverse 1,2,3-thiadiazoles from thiosemicarbazide. Synlett. 2005;(14):2193–5. doi:10.1055/s-2005-871953
34. Dömling A, Ugi I. Multicomponent reactions with isocyanides. Angew Chem Int Ed Engl. 2000;39(18):3168–210. doi:10.1002/1521-3773(20000915)39:18<3168::AID-ANIE3168>3.0.CO;2-U
35. Dömling A. Recent developments in isocyanide based multicomponent reactions in applied chemistry. Chem Rev. 2006;106(1):17–89. doi:10.1021/cr0505728
36. Johansson Seechurn CC, Kitching MO, Colacot TJ, Snieckus V. Palladium-catalyzed cross-coupling: a historical contextual perspective to the 2010 Nobel Prize. Angew Chem Int Ed Engl. 2012;51(21):5062–85. doi:10.1002/anie.201107017
37. Beletskaya IP, Cheprakov AV. The Heck reaction as a sharpening stone of palladium catalysis. Chem Rev. 2000;100(8):3009–66. doi:10.1021/cr9903048
38. Miyaura N, Suzuki A. Palladium-catalyzed cross-coupling reactions of organoboron compounds. Chem Rev. 1995;95(7):2457–83. doi:10.1021/cr00039a007
39. Sonogashira K. Development of Pd–Cu catalyzed cross-coupling of terminal acetylenes with sp2-carbon halides. J Organomet Chem. 2002;653(1–2):46–9. doi:10.1016/S0022-328X(02)01158-0
40. Cravotto G, Cintas P. Power ultrasound in organic synthesis: moving cavitational chemistry from academia to innovative and large-scale applications. Chem Soc Rev. 2006;35(2):180–96. doi:10.1039/B503848K
41. Pinheiro LS, Torres SL, Oliveira SS, Moreira CP, Wanderley AGP. Synthesis, antimicrobial activity, and ADMET evaluation of thiadiazole derivatives. Antibiotics. 2022;11(5):584. doi:10.3390/antibiotics11050584
42. Rezki N, Al-Blewi FF, Aouad MR, Al-Agamy MH, Al-Sehemi AG, Messali M. Synthesis, antimicrobial evaluation, and molecular docking of new thiadiazolyl-triazine hybrids bearing an amino acid moiety. Molecules. 2020;25(3):494. doi:10.3390/molecules25030494
43. Popiołek Ł, Kosikowska U, Mazur L, Malm A, Rajtar B, Polz-Dacewicz M. Synthesis and antimicrobial evaluation of some novel 1,2,4-triazole and 1,3,4-thiadiazole derivatives. Med Chem Res. 2013;22(7):3134–47. doi:10.1007/s00044-012-0302-9
44. Nair YA, Thomas J, Shyjushanker K, Antony S, Sebastian K, Thomas AM. Synthesis, antifungal evaluation, and structure-activity relationship of novel 1,2,3-thiadiazole-piperazine hybrids. Eur J Med Chem. 2018;147:282–93. doi:10.1016/j.ejmech.2018.01.082
45. Pałka K, Bober P, Rzeski W, Popiołek Ł. Novel thiadiazole derivatives as potential antifungal agents against Candida species: synthesis and biological evaluation. Molecules. 2022;27(13):4007. doi:10.3390/molecules27134007
46. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65(1–2):55–63. doi:10.1016/0022-1759(83)90303-4
47. Alam MS, Lee DU. Synthesis and anticancer evaluation of 1,2,3-thiadiazole linked sulfonamide derivatives targeting topoisomerase II and inducing apoptosis. Eur J Med Chem. 2019;167:31–43. doi:10.1016/j.ejmech.2019.01.040
48. Sharma PK, Kumar S, Sharma N, Dudhe R. Synthesis and antiviral activities of thiadiazole nucleoside conjugates. Int J Pharm Sci Res. 2020;11(4):1582–96. doi:10.13040/IJPSR.0975-8232.11(4).1582-96
49. Li X, Zhang S, Yang G, Zhong J. Novel 1,2,3-thiadiazole thioether derivatives as potential antiviral agents: design, synthesis, and biological evaluation. Bioorg Chem. 2019;87:51–61. doi:10.1016/j.bioorg.2019.03.019
50. Kumar D, Sharma R, Bhatt D, Bhardwaj A. In silico screening of thiadiazole derivatives as SARS-CoV-2 main protease inhibitors: molecular docking and ADMET studies. J Biomol Struct Dyn. 2022;40(15):7016–27. doi:10.1080/07391102.2021.1892303
51. Blobaum AL, Marnett LJ. Structural and functional basis of cyclooxygenase inhibition. J Med Chem. 2007;50(7):1425–41. doi:10.1021/jm0613166
52. Patel NB, Khan IH, Pannecouque C, De Clercq E. Synthesis and anti-HIV, antimycobacterial, and antimicrobial screening of thiadiazole derivatives. Med Chem Res. 2012;21(3):317–29. doi:10.1007/s00044-011-9533-4
53. Nair YA, Ramakrishnan V, Thomas J, Antony S. Anti-inflammatory evaluation of novel thiadiazole-sulfonamide hybrids in carrageenan-induced rat paw oedema model. J Pharm Pharmacol. 2018;70(9):1186–98. doi:10.1111/jphp.12948
54. Yadav MK, Srivastava P, Singh J, Yadav SK. Benzothiazole-thiadiazole hybrids as potential anti-diabetic agents: in vitro alpha-glucosidase inhibition and molecular docking studies. J Mol Struct. 2022;1249:131–40. doi:10.1016/j.molstruc.2021.131560
55. Taha M, Imran S, Ismail NH, Rahim F, Wadood A, Khan H, et al. In vitro α-glucosidase inhibitory activity of benzothiazole hybrid thiadiazoles and their molecular docking studies. Bioorg Chem. 2019;84:372–80. doi:10.1016/j.bioorg.2018.11.045
56. Jain S, Pathak D, Bhatt D, Patel A. Design, synthesis, and in vitro antitubercular evaluation of 1,2,3-thiadiazole derivatives against Mycobacterium tuberculosis H37Rv. Med Chem Res. 2019;28(5):1102–13. doi:10.1007/s00044-019-02330-0
57. Bhatt S, Bhatt M, Bhatt R, Bhatt H. Synthesis and antitubercular activity of novel 1,2,3-thiadiazole derivatives against MDR-TB strains. Recent Pat Antiinfect Drug Discov. 2021;16(1):14–31. doi:10.2174/1574891X15999200831095519
58. Desai NC, Bhatt NB, Trivedi AR, Dhaduk MF. Synthesis and in vivo evaluation of central nervous system activity of new 1,2,3-thiadiazole derivatives bearing piperazine moiety. Chem Biol Interface. 2018;8(2):120–30. Available from: https://www.jcbionline.org
59. Kumar A, Narasimhan B, Kumar D. Synthesis, antimicrobial, GABA-A receptor binding, and CNS evaluation of thiadiazole-piperazine hybrids. Eur J Med Chem. 2020;187:111939. doi:10.1016/j.ejmech.2019.111939
60. Monga V, Goyal K, Steinhoff A. Recent advances in pharmacological activities of thiadiazole derivatives: a comprehensive review. Molecules. 2021;26(9):2506. doi:10.3390/molecules26092506
61. Padmaja A, Rajasekhar C, Muralikrishna A, Padmavathi V. Synthesis and antioxidant activity of amino- and hydroxy-substituted 1,2,3-thiadiazoles. Eur J Med Chem. 2011;46(10):5034–8. doi:10.1016/j.ejmech.2011.08.015
62. Consonni V, Todeschini R, Pavan M. Structure/response correlations and similarity/diversity analysis by GETAWAY descriptors. J Chem Inf Comput Sci. 2002;42(3):682–92. doi:10.1021/ci015504a
63. Singh N, Bhatt H. Covalent modification of cysteine residues in drug design: reversible and irreversible strategies. J Med Chem. 2022;65(3):1567–90. doi:10.1021/acs.jmedchem.1c01490
64. Hansch C, Maloney PP, Fujita T, Muir RM. Correlation of biological activity of phenoxyacetic acids with Hammett substituent constants and partition coefficients. Nature. 1962;194(4824):178–80. doi:10.1038/194178b0
65. Brito-Jiménez CM, Flores-Morales V, Tamariz J, Zepeda-Vallejo LG. Hybrid molecules as promising therapeutic alternatives: an overview of recent advances. Mini Rev Med Chem. 2019;19(10):813–26. doi:10.2174/1389557518666181108113413
66. Patel MR, Bhatt KA, Bhatt RG. Synthesis and pharmacological potential of 1,2,3-thiadiazole hybrid scaffolds as dual-acting anti-inflammatory and anticancer agents. World J Pharm Sci. 2020;8(3):120–45. doi:10.20959/wjpps20203-15614
67. Supuran CT. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov. 2008;7(2):168–81. doi:10.1038/nrd2467
68. Sader HS, Flamm RK, Jones RN. Antimicrobial activity of cefazolin tested against staphylococci isolated from patients with surgical site infections in Latin American hospitals. Diagn Microbiol Infect Dis. 2013;75(4):361–4. doi:10.1016/j.diagmicrobio.2013.01.014
69. Ames BN, McCann J, Yamasaki E. Methods for detecting carcinogens and mutagens with the Salmonella/mammalian-microsome mutagenicity test. Mutat Res. 1975;31(6):347–64. doi:10.1016/0165-1161(75)90046-1
70. Sanguinetti MC, Tristani-Firouzi M. hERG potassium channels and cardiac arrhythmia. Nature. 2006;440(7083):463–9. doi:10.1038/nature04710
71. Waring MJ, Arrowsmith J, Leach AR, Leeson PD, Mandrell S, Owen RM, et al. An analysis of the attrition of drug candidates from four major pharmaceutical companies. Nat Rev Drug Discov. 2015;14(7):475–86. doi:10.1038/nrd4609
72. Di L, Kerns EH. Drug-like Properties: Concepts, Structure Design and Methods. 2nd ed. Burlington: Academic Press; 2016. doi:10.1016/C2014-0-00231-4
73. Schneider G, Clark DE. Automated de novo drug design: are we nearly there yet? Angew Chem Int Ed Engl. 2019;58(32):10792–803. doi:10.1002/anie.201814681