Rational Design of 5‘-Thiourea-Substituted α-Thymidine Analogues as Thymidine Monophosphate Kinase Inhibitors Capable of Inhibiting Mycobacterial Growth

Synthesis and inhibitory activity of thymidine analogues targeting Mycobacterium tuberculosis thymidine monophosphate kinase

“…In the 1,4-substituted 1,2,3-triazole series, the anti-TMPKmt activity was clearly influenced by the nature of the substituent at C-4 of the triazole. The click product of AZT and phenylacetylene (8) proved to be more potent than AZT itself. p-Chloro-substitution of the phenyl ring of 8 or introduction of a methylene between the triazole and the phenyl caused a moderate increase in activity (11).…”

“…8 The interactions of the base moiety with the surrounding residues is in inhibitor 3 are similar to the ones with the natural substrate 6 : a stacking with Phe70, H-bond of base atom N3 with Asn100 and base atom O4 hydrogen bonding with Arg74. An additional hydrogen bond involving O3'…”

“…tuberculosis (39% inhibition at 6.25 μg/mL) strains. 8 Next to the relative orientation between the aryl moiety and the nucleobase, structural exploration of the α-thymidine derivatives revealed the importance for aromatic residues at the 5'-position and the positive impact of electronic-withdrawing and lipophilic substituents on the aryl moiety for optimal inhibition of TMPKmt.…”

Towards Understanding Drugs on the Molecular Level to Design Drugs of Desired Profiles

“…the occupancy frequencies of the different atom types (any type, nonpolar, polar-positive charge, polar-negative charge, hydrogen bond acceptor, hydrogen bond donor and aromatic) in the cubic grid cells [33,34]. An example of successful application of the RI-4D-QSAR approach is the study of 5'-arylthiourea thymidine analogues, showing inhibitory activity against thymidine monophosphate kinase from M. tuberculsosis (TMPKmt) [35]. Recently, different RI-and RD-4D-QSAR approaches were successfully applied to a variety of enzyme inhibitors of different drug targets, such as HIV-1 protease [36,37], HIV-1 integrase [38], p38-mitogen-activated protein kinase (p38-MAPK) [39], 14--lanosterol demethylase (CYP51) [40], enoyl-ACP reductase from M. tuberculosis (InhA) [41] etc.…”

“…Thus, differentiation between the cis and trans isomers is essential. Isomers distinction for any platinum compounds showing trans -cis isomerism with 35 Cl-NQR is easy as the difference in the resonance frequencies is high enough and reaches 2.13 MHz: 16.18 MHz for cis-platinum and 18.31MHz for trans-platinum [90]. Another interesting example of NQR capabilities is the study of serine, which occurs in the active sites of many enzymes like chymotrypsin, trypsin and plays an important catalytic function.…”