Design and synthesis of novel HDAC8 inhibitory 2,5-disubstituted-1,3,4-oxadiazoles containing glycine and alanine hybrids with anti cancer activity.
Oxadiazole is a heterocyclic compound containing an oxygen atom and two nitrogen atoms in a five-membered ring. Of the four oxadiazoles known, 1,3,4-oxadiazole has become an important structural motif for the development of new drugs and the compounds containing 1,3,4-oxadiazole cores have a broad spectrum of biological activity. Herein, we describe the design, synthesis and biological evaluation of a series of novel 2,5-disubstituted 1,3,4-oxadiazoles (10a-10j) as class I histone deacetylase (HDAC) inhibitors. The compounds were designed and evaluated for HDAC8 selectivity using in silico docking software (Glide) and the top 10 compounds with high dock score and obeying Lipinski's rule were synthesized organically. Further the biological HDAC inhibitory and selectivity assays and anti-proliferative assays were carried out. In in silico and in vitro studies, all compounds (10a-10j) showed significant HDAC inhibition and exhibited HDAC8 selectivity. Among all tested compounds, 10b showed substantial HDAC8 inhibitory activity and better anticancer activity which is comparable to the positive control, a FDA approved drug, vorinostat (SAHA). Structural activity relation is discussed with various substitutions in the benzene ring connected on 1,3,4-oxadizole and glycine/alanine. The study warranted further investigations to develop HDAC8-selective inhibitory molecule as a drug for neoplastic diseases. Novel 1,3,4-oxadizole substituted with glycine/alanine showed HDAC8 inhibition.
GVK Biosciences Private Limited, IDA Mallapur, Hyderabad, Telangana 500076, India; Department of Biotechnology, Acharya Nagarjuna University, Guntur, Andhra Pradesh 522510, India. Electronic address: pvijayarao@gmail.com.
Vijaya Rao
VR
Pidugu
Department of Biochemistry/Bioinformatics, Institute of Science, GITAM University, Vishakhapatnam, Andhra Pradesh 530045, India.
Nagendra Sastry
NS
Yarla
PRIST University, Thanjavur 613 403, Tamil Nadu, India.
Srinivasa Rao
SR
Pedada
Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana 500046, India.
Arunasree M
AM
Kalle
Department of Biotechnology, Acharya Nagarjuna University, Guntur, Andhra Pradesh 522510, India. Electronic address: akrishnasatya78@gmail.com.
A Krishna
AK
Satya
D000409:Alanine / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005998:Glycine / Q000737:chemistry / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D010069:Oxadiazoles; D012097:Repressor Proteins; C409470:HDAC8 protein, human; D006655:Histone Deacetylases; D000409:Alanine; D005998:Glycine
1,3,4-Oxadiazole; Alanine; Anti-proliferative effect; Class selective; Glycine; HDAC inhibition activity