1,2,3-Thiadiazole thioacetanilides as a novel class of potent HIV-1 non-nucleoside reverse transcriptase inhibitors

Novel 1,2,3-thiadiazole derivatives as HIV-1 NNRTIs with improved potency: Synthesis and preliminary SAR studies

“…13 In the last step, the title compounds 10 were obtained by acylation reaction of 9 with substituted anilines in the presence of 1.1 equiv mol of PCl 5 . However, this route did not give us satisfactory results due to the low overall yield and complicated procedure in these two reaction steps.…”

“…2), which exhibited significant anti-HIV-1 activities. 13 Inspired by these promising results and in continuation of our work on the research of novel NNRTIs, [13][14][15] we thought it is worthwhile to synthesize new compounds of TTAs based on the previous SAR analysis, with the aim to improve the interaction between the inhibitors and RT and to obtain new biologically active molecules.…”

“…On the other hand, it has been demonstrated that the N-substituted phenyl moiety sits at the protein/solvent interface near a region of the protein known to be flexible, 12,13 it might tolerate substitution by structurally diverse groups. Therefore, in several novel molecules, the anilide phenyl ring was also replaced by several substituted heterocycles to further investigate the SARs in this region.…”

“…12,13 This background prompted us to further explore novel TTAs bearing a larger 2,4-dibromo substituted phenyl attached to the 1,2,3-thiadiazole ring. Additionally, in view of the fact that the strength of halogen bonding, 16,17 one of the important interactions in biological molecules, decreases in the order Br > Cl, it is likely that the 2,4-dibromo derivatives could form potentially enhanced halogen bond with carbonyl oxygen in the main chain of residues nearby, and lastly increasing the overall RT-NNRTI binding affinity.…”

Discovery of novel pyridazinylthioacetamides as potent HIV-1 NNRTIs using a structure-based bioisosterism approach

“…Structural and structure-activity relationship (SAR) studies of the known arylazolylthioacetanilides illustrated in the literature [14][15][16][17][18][19][20][21][22] have pointed to the presence of key chemical features that correlated with the RT inhibitory ability, i.e., the aryl group linked to the azole core tted into the important hydrophobic pocket and the carbonyl group of the amide were able to establish a key hydrogen bond through interaction with the backbone N-H of K103. These functionalities are maintained in a spatial arrangement within the NNRTI binding pocket by positioning a heterocyclic central core in the arylazolylthioacetanilides.…”