5-Nitro-2,6-dioxohexahydro-4-pyrimidinecarboxamides: synthesis, in vitro antimycobacterial activity, cytotoxicity, and isocitrate lyase inhibition studies.
Fourteen 5-nitro-2,6-dioxohexahydro-4-pyrimidinecarboxamides (3a-n) were synthesized and evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB), multidrug-resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis (MC(2)), as well as their cytotoxicity and MTB isocitrate lyase (ICL) inhibition activity. 1-Cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl)-4-[(5-nitro-2,6-dioxohexahydro-4-pyrimidinyl)carbonyl]piperazino-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (3n) was found to be the most active compound in vitro with MICs of < 0.17 and 0.17 μM against log-phase MTB and MDR-TB, respectively. Some compounds showed 20-45% inhibition against MTB ICL at 10 μM.
Sriram
Dharmarajan
D
Medicinal Chemistry & Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad, Andhra Pradesh, India. drdsriram@yahoo.com
Yogeeswari
Perumal
P
Senthilkumar
Palaniappan
P
Naidu
Geetanjali
G
Bhat
Pritesh
P
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D002522:Chlorocebus aethiops; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D024901:Drug Resistance, Multiple, Bacterial; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007522:Isocitrate Lyase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009161:Mycobacterium / Q000187:drug effects* / Q000254:growth & development; D020102:Mycobacterium smegmatis / Q000187:drug effects / Q000254:growth & development; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development; D010879:Piperazines; D011485:Protein Binding; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011804:Quinolines; D014376:Tuberculosis / Q000188:drug therapy; D014709:Vero Cells
C556599:1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl)-4-((5-nitro-2,6-dioxohexahydro-4-pyrimidinyl)carbonyl)piperazino-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid; D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D008024:Ligands; D010879:Piperazines; D011743:Pyrimidines; D011804:Quinolines; C402427:icl protein, Mycobacterium; D007522:Isocitrate Lyase