1,3,4-Oxadiazole N-Mannich Bases: Synthesis, Antimicrobial, and Anti-Proliferative Activities

Abstract

The reaction of 5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione 3 with formaldehyde solution and primary aromatic amines or 1-substituted piperazines, in ethanol at room temperature yielded the corresponding N-Mannich bases 3-arylaminomethyl-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 4a–l or 3-[(4-substituted piperazin-1-yl)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 5a–d, respectively. The in vitro inhibitory activity of compounds 4a–l and 5a–d was assessed against pathogenic Gram-positive, Gram-negative bacteria, and the yeast-like pathogenic fungus Candida albicans. The piperazinomethyl derivatives 5c and 5d displayed broad-spectrum antibacterial activities the minimal inhibitory concentration (MIC) 0.5–8 μg/mL) and compounds 4j, 4l, 5a, and 5b showed potent activity against the tested Gram-positive bacteria. In addition, the anti-proliferative activity of the compounds was evaluated against prostate cancer (PC3), human colorectal cancer (HCT-116), human hepatocellular carcinoma (HePG-2), human epithelioid carcinoma (HeLa), and human breast cancer (MCF7) cell lines. The optimum anti-proliferative activity was attained by compounds 4l, 5a, 5c, and 5d.

Antimicrobial Activity and Sar of 2,5-Disubstituted 1,3,4-Oxadiazole Derivatives

“…Al-wahaibi et al (2021) [46] screened 1,3,4-oxadiazole N-mannich bases and tested their antibacterial and antifungal activities against various strains. Antibacterial data revealed that compounds 1 and 2 (ZOI range = 18-30 mm) found to be more active among synthesized compounds and displayed better activity as compared to standard drugs Gentamycin sulfate and Ampicillin trihydrate (Table 1).…”

Antimicrobial Activity of 1,3,4-Oxadiazole Derivatives

“…Compounds 42c-d (Figure 15), in t were only active against Gram-positive strains. Additionally, some of the derivatives played anti-proliferative activity [76]. Moreover, researchers from India led by Neeraja (2016) decided to modify known non-steroidal anti-inflammatory drugs and combine their core with heterocycles (mercapto-1,3,4-oxadiazole and triazole).…”

“…Compounds 42c-d (Figure 15), in turn, were only active against Gram-positive strains. Additionally, some of the derivatives displayed anti-proliferative activity [76].…”

Biological Evaluation and Molecular Docking Studies of Novel 1,3,4-Oxadiazole Derivatives of 4,6-Dimethyl-2-sulfanylpyridine-3-carboxamide

“…It is a bioisostere for carbonyl-containing derivatives, and is also a valid pharmacophore component, increasing the ability of oxadiazole-containing molecules to bind to a various ligands (e.g., muscarinic receptors, benzodiazepine receptors, dopamine, serotonin and norepinephrine transporters) [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. According to the literature, compounds containing 1,3,4-oxadiazole moiety have confirmed various biological effects, including anticancer [ 42 , 43 ], antimicrobial [ 44 , 45 , 46 , 47 ], antidepressant [ 48 ] and anticonvulsant [ 49 ]. Particularly noteworthy is their analgesic and anti-inflammatory activity [ 50 , 51 ], in many cases associated with the inhibition of cyclooxygenase [ 52 , 53 , 54 ].…”