Introduction. It is estimated that annually approximately 10 mln patients are diagnosed with
tuberculosis (TB), of which 558 000 developed multi-drug resistant (MDRT) form of the disease1.
This is considered to be a major problem, as the spreading speed of the MDRT exceeds the studies
and development of new anti-TB solutions. Although several working mechanisms of action are
known among anti-TB drugs, such as enoyl acyl carrier protein reductase (InhA) inhibition, by
activation of mycobacterial enzymes – a catalase/peroxidase, KatG, and a flavin monooxygenase,
EthA. It was proved that Mycobacterium Tuberculosis (MTb) is showing a high genetical
adaptation rate, which is considered the main cause of MDRT development. Current drug discovery
efforts are concentrated on finding inhibition agents of InhA, that do not require activation by KatG
and EthA enzymes and the study of Tryptanthrin alkaloid, with its derivates, are showing good invitro
and in-vivo results, while the molecular docking analysis has demonstrated a good level of
affinity to InhA enzyme.
Materials and methods. Nuclear magnetic resonance spectroscopy (NMR) 1H and 13C
NMR – “Bruker -Avance III” (400.13 and 100.61 MHz). Chemical shifts δ are given in ppm
referring to the signal centre using the solvent peaks for reference: d6-DMSO 2.50 ppm. IR spectra
studied with Spectrum 100 FT-IR spectrophotometer (Perkin - Elmer) using the universal ATR
sampling accessory. Melting points – Boethius apparatus. Thin-layer chromatography – Merck
aluminium sheets, silica gel 60 F254.
Results and discussions. 17 compounds were synthesized based on the original synthesis
schemes2, which were characterized physico-chemically by NMR 1H and 13C NMR, IR
spectroscopy, melting point determination, thin layer chromatography. The biological studies
focused on the determination of the antimycobacterial activity. (5) compound demonstrated the
maximum activity for the 2-(Propylthio)-5H-[1,3,4]Thiadiazolo[2,3-b]Quinazolin-5-One, attributed
to a higher number of hydrophobic interactions with InhA amino acids residues of the S-propyl
derivative2. Acute and subacute toxicity studies were performed for compound (5). No changes in
appearance or behaviour of animals in tested and control groups have been observed. Biochemical
analysis has shown insignificant variations in blood sugar, uric acid, and creatinine concentrations
in serum as compared to the control group. As well, total cholesterol, cholesterol fractions, and
serum transaminases have not shown any significant differences. Toxicity studies allowed us to
conclude that compound (5) can be classified as category five of toxicity according to the guide
OECD 423. Toxicity data has evidenced dose-dependent changes in the lipid metabolism with an
increase in LDL- and total cholesterol. In order to gain insight into the compounds binding mode
and make interpretation of the obtained results, molecular docking was carried out. Analysis of the
obtained compounds’ compliance with the Lipinski rule five has shown that all compounds are
100% compliant.