Thiophene-Linked 1,2,4-Triazoles: Synthesis, Structural Insights and Antimicrobial and Chemotherapeutic Profiles

The reaction of thiophene-2-carbohydrazide <b>1</b> or 5-bromothiophene-2-carbohydrazide <b>2</b> with various haloaryl isothiocyanates and subsequent cyclization by heating in aqueous sodium hydroxide yielded the corresponding 4-haloaryl-5-(thiophen-2-yl or 5-bromothiophen-2-yl)-2,4-dihydro-3<i>H</i>-1,2,4-triazole-3-thione <b>5a</b>-<b>e</b>. The triazole derivatives <b>5a</b> and <b>5b</b> were reacted with different secondary amines and formaldehyde solution to yield the corresponding 2-aminomethyl-4-haloaryl-2,4-dihydro-3<i>H</i>-1,2,4-triazole-3-thiones <b>6a</b>-<b>e</b>, <b>7a</b>-<b>e</b>, <b>8</b>, <b>9</b>, <b>10a</b> and <b>10b</b> in good yields. The in vitro antimicrobial activity of compounds <b>5a</b>-<b>e</b>, <b>6a</b>-<b>e</b>, <b>7a</b>-<b>d</b>, <b>8</b>, <b>9</b>, <b>10a</b> and <b>10b</b> was evaluated against a panel of standard pathogenic bacterial and fungal strains. Compounds <b>5a</b>, <b>5b</b>, <b>5e</b>, <b>5f</b>, <b>6a</b>-<b>e</b>, <b>7a</b>-<b>d</b>, <b>8</b>, <b>9</b>, <b>10a</b> and <b>10b</b> showed marked activity, particularly against the tested Gram-positive bacteria and the Gram-negative bacteria <i>Escherichia coli</i>, and all the tested compounds were almost inactive against all the tested fungal strains. In addition, compounds <b>5e</b>, <b>6a</b>-<b>e</b>, <b>7a</b>-<b>d</b> and <b>10a</b> exhibited potent anti-proliferative activity, particularly against HepG-2 and MCF-7 cancer cell lines (IC₅₀ < 25 μM). A detailed structural insight study based on the single crystals of compounds <b>5a</b>, <b>5b</b>, <b>6a</b>, <b>6d</b> and <b>10a</b> is also reported. Molecular docking studies of the highly active antibacterial compounds <b>5e</b>, <b>6b</b>, <b>6d</b>, <b>7a</b> and <b>7d</b> showed a high affinity for DNA gyrase. Meanwhile, the potent anti-proliferative activity of compounds <b>6d</b>, <b>6e</b> and <b>7d</b> may be attributed to their high affinity for cyclin-dependent kinase 2 (CDK2).