Noteworthy are the 4,5-diaryl-1,2,3-thiadiazole derivatives obtained by Wu et al. due to their method of synthesis and anticancer properties ^[107][122], and results pointed out that compounds 109 and 110 are the lead compounds by exhibiting favorable activity (Figure 13). Growth inhibition rate of tumor cells (obtained from mice S180) by derivative 109 at a dose of 40 mg/kg administrated for 5 days reached 81.0%, while compound 110 displayed a tumor suppression efficacy of 64.2% (at 100 mg/kg of dose administered to mice for five days). These effects were compared with the standard reference CA-4 (combretastatin A-4), which showed a 64.2% antitumor effect at a dose of 40 mg/kg used for 4 days in a mouse model. The SAR study indicated that the reason of the highest antitumor activity of structural motif 109 than reference drug CA-4 and derivative 110 was because of OMe group at C-4 and H at C-3 of 5-phenyl ring of 1,2,3-thiadiazole, while the replacement of hydrogen at C-3 with the nitro group dropped the antitumor activity of derivative 110. The scaffold 109 could be a promising candidate due to its lower cytotoxicity and excellent antitumor effect ^[107][122].

Figure 13.

Antitumor effect of 1,2,3-thiadiales

109

and

110

.

New 1,2,3-thiadiazole derivatives (111 and 112; Figure 14) obtained by Hosny et al. via Hurd–Mori cyclization were tested against MCF-7 tumor cells. The IC₅₀ values of compounds 111 and 112 (IC₅₀ = 12.8 µg/mL and 8.1 µg/mL, respectively) were comparable to doxorubicin as the standard anticancer drug with IC₅₀ = 3.13 µg/mL. The derivative 111 showed the highest anti-breast cancer activity than the scaffold 112 and reference drug doxorubicin ^[108][123].

Figure 14.

Anticancer activity of 2-thioamide-1,2,3-thiadiazole

111

and

112

.

Cikotiene et al. reported the synthetic protocol to achieve the substituted 4,5-diaryl-1,2,3-thiadiazoles as Hsp90 chaperone protein inhibitors. This protein plays a significant part in developing tumor cells, so its inhibition is the main target of many anticancer drugs. The Hsp90 chaperone stabilizes a number of proteins that are essential for the growth of tumors, due to which researchers all over the world are interested in the development of Hsp90 inhibitors which would be investigated as anticancer agents. In the group of tested derivatives, structure 113 deserves special attention as an inhibitor of cancer cells with GI₅₀ value of 0.69 µM for U2OS (osteosarcoma) cells and 0.70 µM for HeLa (cervical carcinoma) cells (Figure 15) ^[109][124]. Isothermal titration calorimetry was used to determine the binding affinity of compound (113) to Hsp90F and Hsp90N. The derivative (39) acted as a binder to both Hsp90N andHsp90F with the observed K_d of about 42 nM and 37 nM, while for the reference compound17-AAG [17-(allylamino)-17-demethoxygeldanamycin] K_d was 200 nM and 240 nM, respectively ^[109][124].

Figure 15.

Anticancer activity of 1,2,3-thiadiazole derivative

113

against U2OS and HeLa cell lines.

Synthesized by Cui et al., dehydroepiandrosterone derivatives of thiadiazoles were investigated against T47D and HAF cell lines for their antitumor activity applying the sulforhodamine B (SRB) assay. In this group of compounds, derivative 114 (Figure 16) focuses particular attention, due to its strong antitumor and antimetastatic activities, in vitro and in vivo. Its IC₅₀ value for T47D cells was 0.058 ± 0.016 µM and for HAF cells IC₅₀ = 21.1 ± 5.06 µM. Moreover, the selectivity of compound 114 (SI = 364) was 214 folds better than adriamycin (positive control) (ADM; SI = 1.7). The SAR study showed that the introduction of 1,2,3-thiadiazole and D-proline chemical entities in derivative 114 significantly enhanced antiproliferative activity than the parent DHEA. The SI of scaffold 114 was 214 folds better than SI of ADM standard drugs. The derivative 114 could be used as the promising and novel class of anticancer agent due to its low cytotoxicity, high selectivity index and excellent antitumor and antiproliferative activities (Figure 16) ^[110][125].

Figure 16.

1,2,3-Thiadiazole dehydroepiandrosterone derivative

114

as new antitumor agents.

2.3. Insecticidal Agents

Insecticides are the designed substances of either chemical or biological origin that used to regulate the insect behaviour, control insects, cause death, dysfunction and moving away ^[111][112][126,127]. Some of the insecticidal agents, such as tebufenozide (115) act as molting hormones primarily against caterpillar pests ^[113][128]; imidacloprid (116) is the most well-known broad spectrum insecticide, which used as an insect neurotoxin ^{[114][115][116]}[129,130,131], and neuroactive pymetrozine (117) is a novel class of pyridineazomethine insecticide used for the control of aphids and whiteflies in crop fields (Figure 17) ^[117][132].

Figure 17.

Known insecticidal agents

115

–

117

.

An interesting example of 1,2,3-thiadiazole derivatives with insecticidal properties are two groups of N-tert-butyl-N,N′-diacylhydrazines obtained by Wang et al. [29] and tested their activity against Plutella xylostella L. and Culex pipiens pallens. Derivative 118 (Figure 18) displayed remarkable and significantly the highest insecticidal potential (79% mortality at 200 μg/mL) against Plutella xylostella L., while 119 exhibited 68% mortality against the same insects at concentration 200 μg/mL. Insecticidal activity of reference agent, i.e., tebufenozide, was 40%. The scaffold 118 displayed excellent and the highest insecticidal potency, 79% more than the insecticidal potencies of reference drug tebufenozide (40%) and derivative 119 (68%). The EWD group chloro increased the insecticidal activity of scaffold 118, while ED group methyl decreased the insecticidal potency of scaffold 119 [29].

Figure 18.

Insecticidal activity of

N

-

tert

-butyl-

N

,

N

′-diacylhydrazines

118

and

119

.

Zhang et al. designed the (E)-β-farnesene based carboxamides of thiadiazoles and checked their aphicidal behavior against Myzus persicae ^[118][133]. The three compound 120–122 (Figure 19) exhibited LC₅₀ values of 33.4 μg/mL, 50.2 μg/mL and 61.8 μg/mL, respectively. The 1,2,3-thiadiazole carboxamide analogues showed significantly higher aphicidal activity than (E)-ß-farnesene, but lesser insecticidal activity than pymetrozine insecticide (LC₅₀ = 7.1 μg/mL). It was observed that fluoro or difluoro groups on phenyl moiety enhanced the aphicidal potential significantly in novel chemical entities of Eβf 1,2,3-thiadiazole 120 and 121 while the methyl substitution led to lower aphicidal activity of scaffold 122 ^[118][133].

Figure 19.

Insecticide Eβf 1,2,3-thiadiazole carboxamides

120

–

112

.

Pyrazole oxime derivatives, as a new Fenpyroximate analogue bearing a thiadiazole moiety, were synthesized by Dai et al. and then their insecticidal, acaricidal and cytotoxic activities were examined. The best insecticidal properties possessed oximes 123 and 124 (Figure 20) against Aphis craccivora at 100 μg/mL with 90% of the mortality rate. The structure–activity relationship study revealed that due to the insertion of F- and Me-groups at p-position of phenoxy moiety attached to the pyrazole oxime 123 and 124 displayed good insecticidal activities but slightly lower than commercial drug imidacloprid ^[119][134].

Figure 20.

Ethers of pyrazole oximes

123

and

124

with insecticidal properties.

Another interesting example of insecticidal compounds are hybrids of substituted triazole and 1,2,3-thiadizole scaffold that were investigated for their activity against Aphis laburni and TMV by Li et al. ^[120][135]. Preliminary bioassays indicated compounds 125 and 126 (Figure 21) as lead compounds by depicting enhanced activity against Aphis laburni at 100mg/mL (mortality ≥ 95%) while the derivative 127 represent the least active compound (due to CF₃ substituted triazole ring) that displayed only 25.25% mortality. The structure–activity study indicated that scaffolds with aromatic moieties attached to the carbonyl carbon of triazole ring have higher insecticidal activity than scaffolds with alkyl moieties ^[120][135].

Figure 21.

Substituted 4-methyl-1,2,3-thiadiazole derivatives with insecticidal properties against

Aphis laburni

.

2.4. Amoebicidal Agents

A parasitic disease caused by a protozoa Entamoeba histolytica is known as amoebiasis. E. histolytica has infected 40 to 50 million people worldwide and led to the development of amoebic colitis or extraintestinal abscess that has resulted in 100,000 deaths annually ^{[121][122][123]}[136,137,138]. The tissue amoebiasis is treated by different drugs such as metronidazole, chloroquine, tinidazole, dehydroemetine and nitazoxanide, while the diloxanide furoate and iodoquinoline drugs are used to treat luminal infections (Figure 22) ^{[124][125][126][127][128]}[139,140,141,142,143].

Figure 22.

Amoebicidal commercial dugs

128

–

130

.

Hayat et al. reported the synthetic route to achieve substituted 1,2,3-thiadiazole scaffolds from the cyclization of quinoline-based hydrazone. All substituted 1,2,3-thiadiazole hybrids and quinoline-based hydrazones were evaluated for antiamoebic activity against HM1 and IMSS strains of E. histolytica. The scaffold 4-bromo phenyl-1,2,3-thiadiazole (131, Figure 23) and furan based 1,2,3-thiadiazole (132, Figure 23) exhibited potent antiamoebic activity (IC50 = 0.24 µM and IC50 = 0.23 µM, respectively) when compared with metronidazole (IC50 = 1.80 µM). The parent intermediate quinoline-based hydrazone displayed better antiamoebic potential than the targeted derivatives of 1,2,3-thiadizoles. The SAR study revealed that the significant loss of antiamoebic potential in scaffolds 131 and 132 was due to the absence of quinoline acetohydrazone moiety in final thiadiazoles ^[129][87].

Figure 23.

The most active antiamoebic 1,2,3-thiadiazoles

131

and

132

.

2.5. Plant Activator Agents

Plant activators are synthetic or natural chemicals entities that protect plants from different pathogens. Among them, pyrimidin-type plant activator 2 (PPA2 133; Figure 24) significantly enhanced plant defense system against bacterial infections unlikely traditional commercially available plant activators (INA 134, BABA 135, BHT 7; Figure 24). Plant activators not only showed their therapeutic potential against wide variety of pathogens but also increased growth of plants, rate of photosynthesis and overall yield of crops ^{[130][131][132][133][134]}[144,145,146,147,148].

Figure 24. Structures of commercially available plant activators 133–135.

Du et al. reported a synthetic pathway for the preparation of carboxylate derivatives of thiadiazoles as potential plant activators against seven plant diseases ^[135][90]. The 1,2,3-thiadiazole derivatives 136 and 137 (Figure 25) proved to be good plant activators and displayed excellent inhibition activities against diseases such as M. melonis, (90% for 136 and 69% for 137), C. cassiicola (77% for 136 and 52% for 137), P. syringae pv. Lachrymans (42% for 136 and 42% for 137) and P. infestans (81% for 136 and 67% for 137) when results were compared with commercial BTH plant activator. The structural motifs 136 and 137 displayed significantly better therapeutic efficacy than BHT commercial drug, but the scaffold 136 had better plant activating potency than scaffold 137 ^[136][88].

Figure 25.

Potential new plant activator with thieno [2,3-

d

]-1,2,3-thiadiazoles

136

and

137

.

2.6. Fungicidal Agents

The chemical agents that have the potential to control and eradicate fungal infections are termed as fungicides or antifungal drugs ^[137][149]. The commercial antifungal agents are chlorothalonil (65) which is a non-systemic fungicide ^[138][139][150,151], fluconazole (66) ^[140][152] and ketoconazole (67) (Figure 26) ^[141][153].

Figure 26.

Structures of commercial antifungal drugs

138

–

140

.

As the first example, it is worth bring up oxadiazoles containing thiadiazole derivatives ^[142][154]. In this group, two oxadiazole derivatives 141 and 142 (Figure 27) displayed the best antifungal activity against Puccinia triticina at a concentration of 500 μg/mL. Both structures showed a remarkable high growth inhibition activity (98 and 83%, respectively) which was slighter lower than the standard drug chlorothalonil with 100% fungal growth inhibition activity. The remarkable high and excellent antifungal activity of scaffold 141 could lead to the development of novel oxadiazole-based 1,2,3-thiadiazole fungicides ^[142][154].

Figure 27.

Novel potent 1,2,3-thiadiazole fungicides

141

and

142

.

Another example of compounds with good antifungal activities are new structures designed by Sun et al., which are 1,2,4-triazole derivatives substituted with a 1,2,3-thiadiazole ring ^[143][82]. One of the synthesized compounds 143 (Figure 28), exhibited remarkably high fungicidal 93.19% against Corynespora cassiicola, while reference compounds iprodione, validamycin and topsin-M possessed 78.20, 53.52 and 78.75% antifungal activity, respectively. The authors declared that compound containing phenyl group on triazole ring 143 exhibited higher activity, however, the results were different in the case of Pseudoperonospora cubensis as compound 144 containing cyclopropyl group displayed higher activity than that of 143. The most active compound with regard to Pseudoperonospora cubensis was 144, which inhibited the growth of this pathogen in 81.62%. However, SAR analysis did not clear the results against pseudomonas syringae pv. Lachrymans. Both the scaffolds showed excellent and the highest antifungal potential than all three commercial reference drugs that will lead to the development of promising antifungal agents ^[143][82].

Figure 28.

Antifungal activity of triazole moiety containing 1,2,3-thiadiazolew

143

and

144

.

Less antifungal activity was observed in the derivative 145 (Figure 29) reported by Tan et al. ^[144][155]. Its inhibition rates to Phytophthora infestans (Mont) de Bary, Alternaria solani, Gibberella sanbinetti, Physalospora piricola Nose, Botrytis cinerea, Phytophthora capsici Leonian, Cercospora arachidicola, Rhizoctonia solanii and Fusarium oxysporum reached 32.3, 17.4, 32.3, 25.8, 43.5%, 36.1, 15.8, 30.3 and 26.9% at 50 μg/mL respectively. The results indicated that the structural motif 145 proved to be broad-spectrum fungicide because it exhibited significant antifungal activity against different fungal strains ^[144][155].

Figure 29.

Piperidine based 1,2,3-Thiadiazole

145

with moderate antifungal activity.

Another group reported the fungicidal properties of 1,2,3-thiadiazole derivatives against Alternaria solani (AS), Botrytis cinerea (BC), Cercospora arachidicola (CA), Cercospora beticola (CB), Colletotrichum lagenarium (CL), Fusarium oxysporum (FO), Gibberella zeae (GZ), Macrophoma kuwatsukai (MK), Phytophthora infestans(Mont) de Bary (PI), Physalospora piricola (PP), Pellicularia sasakii (Shirai) (PS), Puccinia triticina Eriks (PT) and Rhizoctonia solani Kuhn (RS) ^[145][156]. The most active occurred to be structure 146 (Figure 30) showed potent fungicidal inhibitory activity 84.8, 83.9, 83.3, 78.9, 75.0, 71.4, 70.7, 66.7, 64.7 and 63.6% against PS, PP, RS, PT, FO, CB, PI, AS, CL and CA, respectively. On the other hand, the propyl containing fused 1,2,4-triazolo[1,3,4]thiadiazole 147 (Figure 30) exhibited the best fungicidal inhibition activity 93.0% for FO, 84.9% for BC, 77.8% for PS, 75.8% for PI, 75.0% for GZ, 62.1% for CA, 50.0% for CL, 40.5% for PP, 34.4% for AS and 33.3% for CB. The results of the antifungal study showed that fused 1,2,4-triazolo[1,3,4]thiadiazole led to the development of wide-spectrum antifungal agents ^[145][156].

Figure 30.

1,2,3-thiadiazoles with broad antifungal activity.

Wang et al. reported a synthetic approach to new series of organotin 4-methyl-1,2,3-thiadiazole-5-carboxylates and benzo[1,2,3]thiadiazole-7-carboxylates ^[146][157] and antifungal properties against P. piricola and Gibberella zeae. The triethyltin-based 1,2,3-thiadiazole carboxylate analogue 148 (Figure 31) displayed antifungal efficacy EC₅₀ = 0.12 μg/mL and 0.16 μg/mL against P. piricola, and Gibberella zeae, respectively. The overall results of the present study indicated the antifungal effectiveness of organotin-based benzo-1,2,3-thiadiazole or 1,2,3-thiadiazoles analogues proved to be broad-spectrum fungicides ^[146][157].

Figure 31.

Antifungal benzo[1,2,3]thiadiazole-7-carboxylate derivative

148

.

Antifungal properties have also been determined for carboxamide derivatives of thiadiazoles obtained by Zuo et al. utilized one-pot four-component Ugi reaction strategy under green synthetic conditions ^[147][158]. All the synthesized analogues were investigated against eleven fungal strains to develop novel fungicidal candidates. The 1,2,3-thiadiazole containing carboxamide moiety 149 (Figure 32) displayed broad-spectrum fungicidal inhibition activities against CA 71%, AS 100%, GZ 62%, PP 85%, PG 14%, PS, 74%, CL 95%, PI 88% and RS 97%. Similarly good antifungal activity was observed for scaffold 150 that exhibited fungicidal inhibition against various fungal strains such as: CB (Cercospora beticola) 67%, CA 79%, AS 44%, GZ 34%, PP 53%, PG 57%, PS 16%, CL 43%, RS 51% and PI 57%. The scaffold 149 displayed maximum fungicidal potential 100, 97 and 95% against fungal strains AS, RS and CL, respectively, while the zero percent antifungal activity was shown against CB and FO fungal strains, just as scaffold 150 displayed the best antifungal potential 67% against CB fungal strains and 0% against FO ^[147][158].

Figure 32.

The most active 4-methyl-1,2,3-thiadiazole-5-carboxamides.