Synthesis and Biological Evaluation of 1,2,3-Triazole Tethered Thymol-1,3,4-Oxadiazole Derivatives as Anticancer and Antimicrobial Agents

Abstract

A library of 1,2,3-triazole-incorporated thymol-1,3,4-oxadiazole derivatives (<b>6</b>-<b>18</b>) hasbeen synthesized and tested for anticancer and antimicrobial activities. Compounds <b>7</b>, <b>8</b>, <b>9</b>, <b>10</b>, and <b>11</b> exhibited significant antiproliferative activity. Among these active derivatives, compound 2-(4-((5-((2-isopropyl-5-methylphenoxy)methyl)-1,3,4-oxadiazol-2-ylthio)methyl)-1<i>H</i>-1,2,3-triazol-1-yl)phenol (<b>9</b>) was the best compound against all three tested cell lines, MCF-7 (IC₅₀ 1.1 μM), HCT-116 (IC₅₀ 2.6 μM), and HepG2 (IC₅₀ 1.4 μM). Compound <b>9</b> was found to be better than the standard drugs, doxorubicin and 5-fluorouracil. These compounds showed anticancer activity through thymidylate synthase inhibition as they displayed significant TS inhibitory activity with IC₅₀ in the range 1.95-4.24 μM, whereas the standard drug, Pemetrexed, showed IC₅₀ 7.26 μM. The antimicrobial results showed that some of the compounds (<b>6</b>, <b>7</b>, <b>9</b>, <b>16</b>, and <b>17</b>) exhibited good inhibition on <i>Escherichia coli</i> (<i>E. coli</i>) and <i>Staphylococcus aureus</i> (<i>S. aureus</i>). The molecular docking and simulation studies supported the anticancer and antimicrobial data. It can be concluded that the synthesized 1,2,3-triazole tethered thymol-1,3,4-oxadiazole conjugates have both antiproliferative and antimicrobial potential.