2,5-Disubstituted-1,3,4-oxadiazoles/thiadiazole as surface recognition moiety: Design and synthesis of novel hydroxamic acid based histone deacetylase inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2011-10, Vol.21 (19), p.5735-5738
• Main Authors: Rajak, Harish, Agarawal, Avantika, Parmar, Poonam, Thakur, Bhupendra Singh, Veerasamy, Ravichandran, Sharma, Prabodh Chander, Kharya, Murli Dhar
• Format: Article
• Language: English
• Subjects: 1,3,4-Oxadiazoles; 1,3,4-Thiadiazoles; Animals; Anticancer activity; anticarcinogenic activity; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor activity; ascites; Biological and medical sciences; carcinoma; Carcinoma, Ehrlich Tumor - drug therapy; Cell Proliferation; Drug Design; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; enzyme inhibition; General aspects; histone deacetylase; Histone deacetylase inhibitors; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Hydroxamic Acids - chemistry; Medical sciences; Mice; Neoplasms - drug therapy; Oxadiazoles - chemistry; Pharmacology. Drug treatments; Structure-Activity Relationship; structure-activity relationships; Surface Properties; Thiadiazoles - chemistry; Zinc - chemistry
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.08.022

Two novel series of 1,3,4-oxadiazole/thiadiazole analogs were synthesized to meet pharmacophoric structural requirements necessary for HDAC inhibitors, that is, zinc binding group (C), linker (B), and surface recognition cap group (A). Anticancer evaluation using histone deacetylase inhibitors assay, MTT assay, and Ehrlich ascites carcinoma cells in Swiss albino mice exhibited promising results. The enzymatic inhibition of histone deacetylase activity has come out as a novel and effectual means for the treatment of cancer. Two novel series of 2-[5-(4-substitutedphenyl)-[1,3,4]-oxadiazol/thiadiazol-2-ylamino]-pyrimidine-5-carboxylic acid (tetrahydro-pyran-2-yloxy)-amides were designed and synthesized as novel hydroxamic acid based histone deacetylase inhibitors. The antiproliferative activities of the compounds were investigated in vitro using histone deacetylase inhibitory assay and MTT assay. The synthesized compounds were also tested for antitumor activity against Ehrlich ascites carcinoma cells in Swiss albino mice. The efforts were also made to establish structure–activity relationships among synthesized compounds. The results of the present studying indicates 2,5-disubstituted 1,3,4-oxadiazole/thiadiazole as promising surface recognition moiety for development of newer hydroxamic acid based histone deacetylase inhibitor.