Anti-tubercular activities of 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine analogues endowed with high activity toward non-replicative Mycobacterium tuberculosis.
Thirty three derivatives of 2-substituted 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine analogues were synthesized by molecular modification of a reported antimycobacterial molecule (GSK163574A). Compounds were evaluated in vitro against actively replicative and nutrient starved non-replicative Mycobacterium tuberculosis (MTB), enzymatic screening and cytotoxicity against RAW 264.7 cell line. Among the compounds, 2-ethyl-N-phenethyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine (5c) was found to be the most active compound against non-replicative MTB with 2.7 log reduction of bacteria at 10μg/mL and was more potent than isoniazid (1.2 log reduction) and rifampicin (2.0 log reduction) at same dose level. Compound 5c also showed activity against MTB alanine dehydrogenase enzyme with IC50of 1.82±0.42μM and showed 25% cytotoxicity against RAW 264.7 cell line at 50μg/mL.
Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawaharnagar, Hyderabad 500078, India.
Ganesh
G
Samala
Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawaharnagar, Hyderabad 500078, India.
Parthiban
P
Brindha Devi
Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawaharnagar, Hyderabad 500078, India.
Shalini
S
Saxena
Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawaharnagar, Hyderabad 500078, India.
Saritha
S
Gunda
Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawaharnagar, Hyderabad 500078, India.
Perumal
P
Yogeeswari
Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawaharnagar, Hyderabad 500078, India. Electronic address: dsriram@hyderabad.bits-pilani.ac.in.
Dharmarajan
D
Sriram
D050788:Alanine Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
C000621634:5,6,7,8-tetrahydrobenzo(4,5)thieno(2,3-d)pyrimidin-4-amine; D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D013876:Thiophenes; D050788:Alanine Dehydrogenase
Dormant tuberculosis; Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine analogues; Tuberculosis; l-Alanine dehydrogenase