title: Synthesis and HIV-1 RT inhibitory action of novel (4/6-substituted benzo[d]thiazol -2-yl)thiazolidin-4-ones. Divergence from the non-competitive inhibition mechanism.
abstract: Reverse transcriptase (RT) inhibitors play a major role in the therapy of human immunodeficiency virus type 1 (HIV-1) infection. Although, many compounds are already used as anti-HIV drugs, research on development of novel inhibitors continues, since drug resistant strains appear because of prolonged therapy. In this paper, we present the synthesis and evaluation of HIV-1 RT inhibitory action of eighteen novel (4/6-halogen/MeO/EtO-substituted benzo[d]thiazol-2-yl)thiazolidin-4-ones. The two more active compounds (IC50 : 0.04 µM and 0.25 µM) exhibited better inhibitory action than the reference compound, nevirapine. Docking analysis supports a stable binding of the most active derivative to the allosteric centre of RT. Kinetic analysis of two of the most active compounds indicate an uncompetitive inhibition mode. This is a desired characteristic, since mutations that affect activity of traditional non-competitive NNRTIs may not affect activity of compounds of this series. Interestingly, the less active derivatives (IC50 > 40 µM) exhibit a competitive mode of action.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Pitta
authors.forename: Athina
authors.initials: A
authors.lastname: Geronikaki
authors.forename: Sofiko
authors.initials: S
authors.lastname: Surmava
authors.forename: Phaedra
authors.initials: P
authors.lastname: Eleftheriou
authors.forename: Vaibhav P
authors.initials: VP
authors.lastname: Mehta
authors.forename: Erik V
authors.initials: EV
authors.lastname: Van der Eycken
mesh_terms: D060326:Chemistry Techniques, Synthetic; D004353:Drug Evaluation, Preclinical / Q000379:methods; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007700:Kinetics; D062105:Molecular Docking Simulation; D019829:Nevirapine / Q000494:pharmacology; D009570:Nitriles; D011724:Pyridazines / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000737:chemistry; D018675:Toxicity Tests
chemical_list: D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D053778:Thiazolidines; C451734:etravirine; D019829:Nevirapine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase