An Explicative Review of Thiadiazole: Medicinal Chemistry Aspects

Compounds that are cyclic containing carbon atoms and another element atom, that are sulfur, oxygen, and nitrogen in the ring are known as heterocyclic compounds. These heterocyclic compounds show great interest in our life. Their nucleus is found in many biologically active compounds. Thiadiazole is an example of a heterocyclic compound.

The significant 5-membered heterocyclic ring thiadiazole has 2 nitrogen and 1 sulfur atoms as heteroatoms. The general formula of thiadiazole is C₂H₂N₂S. Four different structures are available depending on the relative placements of the heteroatoms; these forms are structural isomers because they do not interconvert. 1,3,4-thiadiazole is the most common and appears in several medications.

Figure 1: Different thiadiazole isomers Click here to View Figure

In comparison to pyridine, benzene, and thiophene, the ring structure is less aromatic. The π electron delocalization is used to quantify the aromatic character. Because nitrogen atoms withdraw electrons, nucleophilic substitution reactions occur often whereas electrophilic attack at carbon is quite uncommon. There has been evidence of electrophilic bombardment at the sulfur atom. 1,3,4-thiadiazoles are easily acylated and alkylated because of the inductive effects of additional heteroatoms. In aqueous acid solutions, the ring is rather stable, but in aqueous basic solutions, it cleaves. thione-thiol or amine-imine equilibrium of tautomeric determines the electrophilic processes that give rise to the ring reactivity of nitrogen atoms. Deprotonation of the ring atom (nitrogen) can occur in the thione or imine form, making the ring atom (nitrogen) susceptible to acylation, alkylation or transformation into 1,3,4-thiadiazolium salt. Electrophiles including alkyl halides, trimethylsilylmethyl trifluoro methanesulfonate, and formaldehyde are used in the processes. 1, 3, 4-thiadiazole core skeletons undergo a variety of replacement processes involving sulfonyl chlorides, acid chlorides and alkyl halides to produce a range of drugs, including 2-amino substituted 1,3,4-derivatives of thiadiazole.

Structural isomers that have a different double bond and differ in proton locations are known as tautomerism. Their carbon backbone remains the same.^1-3

Figure 2: Tautomerism in thiadiazole Click here to View Figure

Antioxidant Properties

Malak Ajit Sajid et al. (2024) Describe a fusion of 1,3,4 Thiadiazole substituted Schiff bases. The synthesised compounds were characterised by Mass spectroscopy, FTIR, 1HNMR and 13CNMR. These compounds were tested for antioxidant activity. Among all compounds,3b (Fig 3) gives excellent activity.⁴

Figure 3 Click here to View Figure

Rakesh Kumar Marwaha et al.(2023) reported a synthesis of thiadiazole derivatives as an antioxidant property through a DPPH assay. Among the synthesised compounds, AZ-15  (Fig.4) shows good potential compared with standard drug (ascorbic acid). (IC₅₀: 42.88). ⁵

Figure 4 Click here to View Figure

Cakmak Sukriye et al. (2023) describe the synthesis of thiadiazole derivatives as an antioxidant activity. Compound II (Fig.5) shows greater ABTS⁺ radical scavenging capacity. [IC₅₀:68.93]⁶

Figure 5 Click here to View Figure

Amer Zainab et al. (2022) reported thiadiazole derivative compound 2d (Fig.6) as an antioxidant whose scavenging percentage of 69.07% at 50 mg/mL.⁷

Figure 6 Click here to View Figure

Yakan Hasan (2020) provided the synthesis of thiadiazole derivatives. Synthesised molecule’s in-vitro antioxidant properties were determined by the DPPH process. They observed that the II molecule (Fig.7) shows potent antioxidant properties with IC₅₀ 25.17 μg/mL.⁸

Figure 7 Click here to View Figure

Hacer Bayrak et al. (2019) reported the synthesis of a novel compound of imidazole[2,1-b][1,3,4-]thiadiazole (ITD). These compounds were tested for antioxidant activity. The compounds 2 (IC₅₀7.05), 3a (IC₅₀1.14), and 3b (IC₅₀3.37) show more prominent antioxidant activity than Trolox, a standard drug.¹³

Figure 8 Click here to View Figure

Figure 9 Click here to View Figure

Figure 10 Click here to View Figure

Kamboj Kumar Vipan et al. (2019) reported a synthesis of derivatives of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole was performed. Compound TH-13 was found to have antioxidant activity, which is better than the standard compound. The IC₅₀ value of the compound is   8.1 ± 0.325 μg/mL.⁴⁴

Figure 11 Click here to View Figure

Markovic Violeta et al. (2019) reported a synthesis of 15 new 1,3,4-thiadiazole derivatives that have protocatechuic acid moiety present in them. The antioxidant property was determined by the DPPH and ABTS assays. Among these 15 compounds, 3c shows better antioxidant properties with an IC₅₀ value of 3.53 μg/mL.⁴⁷

Figure 12 Click here to View Figure

Gowda Kemparaje et al. (2019) reported the synthesis of a group of 2,5-disubstituted 1,3,4 compounds and tested for antioxidant properties. Among the synthesized compounds 4k shows excellent antioxidant properties. Molecular docking was performed to check the binding property of 4k with proteins.⁴⁶

Figure 13 Click here to View Figure

Rabie M. Amgad et al. (2018) reported thirteen compounds of 1,3,4-thiadiazole-2-thiols. These structures were synthesised and evaluated for antioxidant activities. The structure of these compounds was established by spectroscopy and chemical analysis. Three compounds (3b,d,h) show promising antioxidant activity.⁴⁵

Figure 14 Click here to View Figure

Figure 15 Click here to View Figure

Figure 16 Click here to View Figure

Structure-Activity Relationship

The above literature survey tells that SAR of derivatives of thiadiazole for Antioxidant activity exists due to the presence of the NH₂ group at the para position in the compound AZ-15 (4-(4-aminophenyl)-1-(5-(4-bromophenyl)-thiadiazole-2yl)-3-chloroazetidin-2-one). Presence of allyl group (-CH2CH=CH2) increase the activity in Compound II (N5, N5’-diallyl-[2,2’-bi(1,3,4-thiadizole)]-5,5’-diamine). This literature survey also revealed the presence of electron-donating groups such as NH₂, and OCH₃ that can act as free radicals and inhibit the oxidation process increasing antioxidant activity like in compound 2d. presence of an E.W.D such as fluorine which withdraws electrons by inductive effect, causing electron density to reduce. This helps in the easier loss of proton as shown in compound II.

Anti-inflammatory Properties

Zaharia Valentin et al. (2024) reported that Reverse-phase thin-layer chromatography was used to conduct the experimental lipophilicity study in a binary isopropanol-water mobile phase. The theoretical lipophilicity parameters derived using different computational techniques were compared with the observed results. They synthesise 32 heterocyclic compounds among which 1b-16b are imidazo[2,1-b][1,3,4]thiadiazoles derivatives. Compounds having excellent antioxidant activity after evaluating lipophilicity and POM analysis are 1b, 4b, 5b,9b, 12b, and 13b. these compounds show an excellent reduction in acute inflammation in vivo.^25,27

Figure 17 Click here to View Figure

Figure 18 Click here to View Figure

Figure 19 Click here to View Figure

Figure 20 Click here to View Figure

Figure 21 Click here to View Figure

Figure 22 Click here to View Figure

Dhadde Shivsharan et al.(2024) reported the synthesis of new derivatives of N-{[5-(substituted)-1,3,4- thiadiazole-2-yl] carbamothioyl}. These compounds were synthesised using a green chemistry approach assisted by microwave. Compounds were tested for anti-inflammation properties. A carrageenan-induced paw edema model in rats were used to check the anti-inflammatory activity. All synthesis compound shows remarkable anti-inflammatory properties. 1b shows a greater anti-inflammatory property. At 50mg/kg dose, 1b shows 50% depletion in paw edema volume.²⁶

Figure 23 Click here to View Figure

El-Saghier M. Ahmed et al.(2024) reported the synthesis of 1,3,4-thiadiazole derivatives having carboxamide. The newly synthesised compounds were subjected to an anti-inflammatory test (protein denaturation). Among all compounds, three compounds show excellent inhibition properties. These compounds are 4c, 3a, 8c.²⁸

Figure 24 Click here to View Figur

Figure 25 Click here to View Figure

Figure 26 Click here to View Figure

Shaik B. Afzal et al. (2024) reported the synthesis of thiadiazole derivatives containing a pyridine base. They were tested for anti-inflammatory properties. Among all compounds, NTD3 shows excellent results in anti-inflammatory properties.²⁹

Figure 27 Click here to View Figure

Shakirzyanova S.G et al.(2024) reported a synthesis of 5,5-(Disulfanediyl)bis[3-phenyl-1,3,4-thiadiazole-2(3H)-thione](1). Compound was tested for anti-inflammatory property. The anti-inflammatory test was conducted using the carrageenam footpad edema model. They concluded that the compound showed activity at doses of 10mg/kg.³⁰

Figure 28 Click here to View Figure

Haroun Michelyne et al.(2023) reported the synthesis of new 5-andamathylthiadiazole-contain thiazolidinone derivatives. These derivatives were examined for anti-inflammatory activity and havean excellent gastric profile. Four compounds show excellent antioxidant activity compared to the indomethacin(control drug). These compounds are 3,4,10, and 11.³¹

Figure 29 Click here to View Figure

Figure 30 Click here to View Figure

Figure 31 Click here to View Figure

Figure 32 Click here to View Figure

Omar M. Yasser et al.(2020) reported the synthesis of 1,3,4-thiadiazole and 1,3-thiazolidin-4-one derivatives among the synthesis compounds compound 3a,4r and 4q gives excellent anti-inflammatory activity in in vivo study.³²

Figure 33 Click here to View Figure

Figure 34 Click here to View Figure

Figure 35 Click here to View Figure

Pathak Prateek et al.(2019) reported a synthesis of 1,2,4-triazole-containing 1,3,4-thiadiazole hybrid compounds and tested these compounds for their anti-inflammatory activity. 13f and 13g are the most potential compounds of all.³³

Figure 36 Click here to View Figure

Figure 37 Click here to View Figure

Mehta K. Dinesh et al.(2019) synthesis of thiadiazole derivatives and tested for anti-inflammatory activity. Compounds 6d.6i,6j and 6l show excellent antioxidant activity.³⁴

Figure 38 Click here to View Figure

Figure 39 Click here to View Figure

Figure 40 Click here to View Figure

Figure 41 Click here to View Figure

Abdu-Allah M.H. Hajjaj et al.(2018) reported the synthesis of Thiazolidinone-thiadiazole derivatives containing 5-alk/arylidene. Synthesised compounds were tested for anti-inflammatory activity. Three compounds show excellent anti-inflammatory activity. These compounds were 6a,6l and 9.³⁵

Figure 42 Click here to View Figure

Figure 43 Click here to View Figure

Figure 44 Click here to View Figure

Structure-activity Relationship

The following literature survey shows that the presence of a 4-benzenesulfonamide compound at C-2 of imidazole[2,1-b][1,3,4]-thiadiazole is essential to linking with COX-2 inhibitors, as seen by Zaharia Valentin et al.’s report. On the thiadiazole ring, electron-donating groups such as methyl and phenyl increase the inflammatory activity. Similarly, electron-withdrawing groups decrease the inflammatory activity. N.Podila et al. Reported that the presence of phenyl carboxylate at C-5 of thiadiazole having pyridine at C-2 shows greater anti-inflammatory activity than having phenyl attached to C-5.

Antimicrobial Properties

Saki Neslihan et al. (2022) describe 1,3,4- thiadiazole derivatives synthesis that contain the thiophene group as an antibacterial molecule. Antibacterial activity is determined using well diffusion, TLC-Dot blot, growth curve and macro dilution analytical methods. Compounds 1 (Fig.9) and 6 (Fig.10) show remarkable antibacterial activity, as opposed to gram-positive and negative bacteria.⁹

Figure 45 Click here to View Figure

Figure 46 Click here to View Figure

Gidwani Bina et al. (2021) show in their study, the synthesis of 1,3,4-thiadiazole by cyclisation. The synthesised compound has benzaldehyde groups. All compound shows promising activity but compound II shows excellent activity against gram+ and gram-bacteria.⁴¹

Figure 47 Click here to View Figure

Khanum ara shaukath et al. (2020) Give a synthesis of substituted thiadiazole. These compounds were examined for antimicrobial activity. Compound 5b (Fig11) among all compounds shows excellent antimicrobial properties.¹⁰

Figure 48 Click here to View Figure

Ibrahim G. Ahmed (2020) reported a synthesis of two polymers. These two polymers are 1,3,4-thiadiazole molecules linked with chitosan. They were tested for antimicrobial growth. They inhibit the growth of P. aeruginosa, S. aureus, E. coli, and B. subtilis. MIC value of Cs-EATT (Fig.13) (polymer) is in the scale of 25–100 µg mL^–1 and Cs-BATT (Fig.14) (polymer) is in the scale of 25–200 µg mL^–1.¹²

Figure 49 Click here to View Figure

Figure 50 Click here to View Figure

Gomha M. Sobhi et al. (2019) reported a group of 1,3,4-thiadiazole derivatives. These compounds were checked for antimicrobial properties. Among all the synthesized compounds 6b shows excellent properties.¹¹

Figure 51 Click here to View Figure

Bayrak Hacer et al. (2019) published a synthesis of imidazole thiadiazole (ITD) derivatives that are examined for antimicrobial activity. Compound 3b (Fig.15) shows excellent antimicrobial activity. It is a chloride derivative of ITD. It shows great activity against gram-negative and positive bacteria. ¹³

Figure 52 Click here to View Figure

Abdallah A.Magda et al. (2012) reported a group of compounds having 1,3,4-thiadiazole moiety. These compounds were examined for antimicrobial activity. All compounds give excellent results. Compounds 7a,7c, and 7d give positive results against all bacteria used for the evaluation. Four different bacterial colonies are used to test antimicrobial activity, these are  Bacillus subtilis (RCMB 000107, BS), Staphylococcus aureus (RCMB 000106, SA), Escherichia coli (RCMB 000103, EC), and Pseudomonas aeruginosa (RCMB 000102, PA).⁴²

Figure 53 Click here to View Figure

Figure 54 Click here to View Figure

Figure 55 Click here to View Figure

Foroumadi Alireza et al.(2011) reported the synthesis of 1,3,4-thiadiazole derivatives containg imidazole. These compounds were examined for antimicrobial properties. Among all, compound 6b gives promising activity against Bacillus subtilis,Staphylococcus aureus, and Staphylococcus epidermidis.⁴⁹

Figure 56 Click here to View Figure

Kotresh Oblennavar et al. (2010) designed an effective route to synthesise 1,3,4-thiadiazole derivatives. The synthesised compound were tested for antimicrobial activity. Three compounds show excellent activity from others. These compounds are 3h(Fig:58), 3f(Fig:59), 3e(Fig:60).⁴⁸

Figure 57 Click here to View Figure

Figure 58 Click here to View Figure

Figure 59 Click here to View Figure

Profire Lenuta et al. (2007) published the synthesis of 1,3,4- thiadiazole having D, L-methionine moiety. These compounds were examined for antimicrobial effect by using Bacillus antracis ATCC 8705, Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, Bacillus cereus ATCC 10987, and Sarcina lutea ATCC 9341 strains. Amongst all 5c shows excellent antimicrobial activity against Bacillus cereus and Bacillus antracis.⁴³

Figure 60 Click here to View Figure

Structure-Activity Relationship

The literature survey indicated that the electron-donating group decreased the antimicrobial activity. If the hydrophobic character of R increases it increases the activity except if electron density increases at the π-π interaction it decreases the activity. Less hindered group present on R gives potential activity. The electron-donating group decreases the activity. The present literature survey indicates the presence of two different aromatic rings with two Bromo at the ortho part of the aromatic ring attached to the thiadiazole structure giving excellent activity.

Anticancer properties

Osmaniye Derya et al. (2020) Give the synthesis of 1,3,4-thiadiazole descendant as chemotherapeutic compounds. Compound 4i (Fig.16) demonstrates possible action against the rat brain cancer cell line C6 with IC50 0.097mM. ¹⁴

Figure 61 Click here to View Figure

Cevik Acar Ulviye et al. (2020) composed the substituted thiadiazole derivative. these compounds were investigated for anticancer activity. Among all compounds, 4y (Fig17) shows incredible cytotoxic ability opposite to MCF7 cancer cells. [IC50: 0.084±0.020.] ¹⁵

Figure 62 Click here to View Figure

Emami Saeed et al. (2020) Tell a synthesis of ciprofloxacin derivative modified at C-3. The maximum compound shows remarkable properties against several cancer cells in the MTT assay. Compounds 13e (Fig.18) and 13g (Fig.19) show excellent anticancer activity.¹⁶

Figure 63 Click here to View Figure

Figure 64 Click here to View Figure

Raju Ramesh Rudraraju et al. (2020) reported a group of amides containing thiadiazole triazole compounds. These compounds were synthesised and tested for anticancer activity. Among all compounds, 8b (Fig.20) shows excellent activity against A549 (0.17±0.032μM), DU-145 (0.83±0.091μM), MCF-7(0.10±0.084μM), and MDA MB-231 (0.28±0.017 μM). ¹⁷

Figure 65 Click here to View Figure

Antidiabetic

Rehman Wajid et al. (2022) tell of the synthesis of 25 newly two fused thiadiazole having 1,4-benzodioxine compounds. These compounds were tested for antidiabetic activity. Among all compounds, 22 (Fig21) show great activity.¹⁸

Figure 66 Click here to View Figure

Singh Parvesh et al. (2021) discloses the synthesis of a thiazolidine-4-one carrying 1,3,4- thiadiazole. The compound was tested for antidiabetic. Among all compounds, 4e (Fig 22) shows promising activity. ¹⁹

Figure 67 Click here to View Figure

Cui Zi-Ning et al. (2021) put out the union of 2,5-disubstituted furan derivatives have 1,3,4-thiadiazole derivatives antidiabetic activity. Compound 9 (Fig.23) shows excellent inhibitory properties with an IC₅₀ value is 0.186µM. ²⁰

Figure 68 Click here to View Figure

Hameed A. Sherin et al. (2020) reported a group of 5-furyl-1,3,4-thiadiazole-2-imine derivatives as antidiabetics. Among all compounds, SA03 (Fig.24) and compound SA07(Fig.25) have high docking scores and a good percentage of inhibiting alpha-amylase. ²¹

Figure 69 Click here to View Figure

Figure 70 Click here to View Figure

Structure-activity relationship (SAR)

The above literature survey indicates that the presence of dihydroxy on the ortho, meta site of the phenyl ring gives significant α-amylase and α-glucosidase activity in compound 22 of  Rehman Wajid et al. electron-donating nature of thiomethyl at para position gives high binding affinity for α-glucosidase. 4e which has a thiomethyl unit at the para position shows great activity. Substituting R at phenyl is essential for activity as it was observed in compound 9 which shows greater activity. Hameed A. Sherin et al observed that compounds having electron-donating groups at the phenyl ring at 2 and 4^th position (SA03) and furyl ring (SA07) attached to the imine bond give higher biological activity.⁵⁰

Conclusion

This analysis has delivered comprehensive insights into thiadiazole, with a particular focus on 1,3,4-thiadiazole. In this review, we examine the antioxidant, antimicrobial, and anticancer properties of thiadiazole derivatives. Modifications to the thiadiazole structure lead to compounds with notable pharmacological effects, which may eventually serve as effective therapeutic agents. While the primary clinical applications include antibacterial, antifungal, carbonic anhydrase inhibition, and anticancer activities, there remain additional potential targets yet to be investigated. Although various positions have been explored to enhance the efficacy of 1,3,4-thiadiazole, none of the derivatives have demonstrated significant antitubercular activity. The literature has been thoroughly reviewed to offer a substantial overview of the structural prerequisites for activity, wherever applicable.

Acknowledgment

We would like to express our gratefulness to the Department of Pharmaceutical Chemistry GCRG College of Pharmacy, Lucknow, U. P. India.

Conflict of Interest

The authors declare that there is no conflict of interest regarding the publication of this article.

Funding Sources

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Data Availability Statement

Information can be accessed upon request.

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