# Synthetic Transformations and Medicinal Significance of 1,2,3-Thiadiazoles Derivatives: An Update
## 2 Synthetic Approaches
### Antiviral Agents  
[PERSON] et al. described antiviral drugs as such bioactive compounds which are used for the treatment of viral infections [96]. [PERSON] et al. reported that most of the antiviral agents are specifically targeted oriented while some other antivirals have a broad spectrum against a vast variety of viral infections [97]. Some antiviral drugs such as ribavirin (**89**; Figure 3) are being used against both RNA and DNA viruses [98-100], efavirenz (**90**; Figure 3) used for the treatment of HIV/AIDS [101-103] and arbidol (**91**; Figure 3) was used against influenza viruses [104,105]. [PERSON] et al. prepared 1,2,3-thiadiazole thioacetanilide by adopting a multi-step methodology and exhibited their anti-HIV (Human Immunodeficiency Virus) activity against MT-4 cells. Among all synthesized derivatives, the thioacetanilide based 1,2,3-thiadiazole scaffold (**92**; Figure 4) showed remarkably the best anti-HIV activity in terms of EC\({}_{50}\) value 0.059 \(\pm\) 0.02 \(\upmu\)M, CC\({}_{50}\)\(>\) 283.25 \(\upmu\)M, SI \(>\) 4883 \(\upmu\)M compared to the reference compounds such as NVP (nevirapine) DLV (delaviridine), EFV (Efavirenz), AZT (azidothymidine) and VRX-480773. SAR displayed that the significant enhancement in the antiviral efficacy of compound **92** was due to the introduction of the nitro group on the phenyl ring. Anilide scaffold having NO\({}_{2}\) and halogen-substituted aryl ring at \(o\)-position took great part to enhance the anti-HIV potential, however, the case was the difference for fluorine atom which decreased activity at a certain level [106]. [PERSON] et al. prepared potent 1,2,3-thiadiazole derivatives against HIV-1. The new 1,2,3-thiadiazole (**93**; Figure 5) proved as the most active anti HIV-1 agent (EC\({}_{50}\) value 0.0364 \(\pm\) 0.0038 \(\upmu\)M, CC\({}_{50}\)\(>\) 240.08 \(\upmu\)M and SI \(>\) 6460 \(\upmu\)M) against MT-4 cells among the synthesized derivatives in comparison with the reference compounds NVP (EC\({}_{50}\) 0.208 \(\upmu\)M) and DLV (EC\({}_{50}\) 0.320 \(\upmu\)M) EFV (EC\({}_{50}\) 0.00440 \(\upmu\)M) and AZT (EC\({}_{50}\) 0.0151 \(\upmu\)M). Phenyl ring substituted with 2,4-Br\({}_{2}\) group significantly increased the antiviral potential of compound **93** than all other substituents on the phenyl ring. SAR studies indicated decreasing order of antiviral strength, i.e., 2,4-Br\({}_{2}\)\(>\) 2,4-Cl\({}_{2}\)\(>\) 2,4-F\({}_{2}\)[107]. [PERSON] et al. prepared potent antiviral piperidine-based thiadiazole derivatives, and the SAR study showed that chlorine atom substituted compounds exhibited good antiviral activity and the substitution on phenyl ring affects inhibitory action. 1,2,3-thiadiazole (**94**; Figure 6) displayed excellent potency with IC\({}_{50}\) 3.59 \(\upmu\)g/mL as compared to lamivudine (IC\({}_{50}\) value 14.8 \(\upmu\)g/mL). It was observed that compounds having \(p\)-substituents exhibited more cytotoxic potency than the \(o\)-substituted derivatives. Moreover, lowering of the selective index with higher anti-HBV potencies of the synthesized compounds was observed when comparing the results with lamivudine. Compound **94** proved to be the most active one as compared to the other derivatives [86]. Figure 4: Thioacetanilide based 1,2,3-thiadiazole scaffold **92** exhibiting maximum anti-HIV potential. Figure 3: Structures of antiviral drugs **89–91**. Synthesis and screening of antiviral potency of tetrazole-based 1,2,3-thiadiazoles structural against tobacco mosaic virus (TMV, anti-TMV) were evaluated [84]. The studies indicated that some obtained compounds (**95-98**; Figure 7) have higher anti-TMV activity (33.75-48.73%) than ribavirin at 100 mg/mL concentration (33.23%) and comparable potency to ribavirin at 100 ug/mL. Structure **97** displayed the best protection effect among the synthesized derivatives as well as from the ribavirin--reference drug.