Parallel Solution-Phase and Microwave-Assisted Synthesis of New S-DABO Derivatives Endowed with Subnanomolar Anti-HIV-1 Activity

Abstract

A simple and efficient methodology for the parallel solution-phase synthesis has been set up to obtain a series of thiouracils, in turn selectively S-benzylated under microwave irradiation to give new S-DABOs. Biological screening led to the identification of compounds with nanomolar activity toward both the highly purified recombinant human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) enzyme (wild-type and mutants) and wild-type (wt) and mutant HIV-1 strains. In particular, 20 was found to be the most potent S-DABO reported so far (ID50 = 26 nM toward the isolated wt enzyme) with subnanomolar activity toward both the wt and the pluriresistant virus (IRLL98) HIV-1 strain (EC50 < 0.14 nM and EC50 = 0.22 nM, respectively). Molecular modeling calculations were also performed to investigate the binding mode of such compounds onto the non-nucleoside reverse transcriptase inhibitor binding site and to rationalize the relationships between their chemical structure and activity values toward wt RT.

Synthesis and Biological Evaluation of Some Novel Polysubstituted Pyrimidine Derivatives as Potential Antimicrobial and Anticancer Agents

“…The thrust in derivatization of such scaffold was focussed on the thione function that was linked to a variety of pharmacologically active substituents and functionalities through -CH 2 -or -CH 2 CO-bridges, or directly hooked to the sulfur atom to produce the target thioethers. Thioethers were found to show enhanced antimicrobial and antitumor activities [35 -37], beside being analogs of SDABOs (dihydro-alkylthio-benzyl-oxopyrimidines) which possess antiproliferative as well as antiviral activities [38,39]. Moreover, at a certain stage of this investigation, the synthesis of chloropyrimidines was planned owing to their reported potential antimicrobial and antitumor activities [40,41].…”

Towards new methodologies for the synthesis of biologically interesting 6-substituted pyrimidines and 4(3H)-pyrimidinones

“…[48][49] The new compounds were evaluated in enzymatic tests for their ability to inhibit either wild-type (wt) or mutated RTs as well as on MT-4 cells for cytotoxicity and anti-HIV-activity, in comparison with nevirapine (nev) and efavirenz (efa), used as reference drugs. In particular, the following mutants were used: K103N and Y181I for enzymatic tests, K103N, Y188L, and pluriresistant virus (IRLL98) (bearing the K101Q, Y181C, and G190A mutations conferring resistance to nev, delavirdine, and efa, respectively) for tests on cell lines.…”

Microwave-assisted synthesis of thermo- and pH-responsive antitumor drug carrier through reversible addition–fragmentation chain transfer polymerization

“…For example, Imatinib (Gleevec), a marketed anticancer drug, can be produced through microwave heating in five steps with shorter reaction times and higher yields than what can be obtained through traditional heating methods [5]. Various inhibitors and pharmaceutical molecules have been synthesized through microwave-assisted synthetic protocols to treat infectious diseases such as tuberculosis, HIV/AIDS, malaria, and hepatitis C [6][7][8][9]. Other notable examples, including biologically active heterocycles for Sildenafil analogs [10,11], nontoxic biofilm inhibitors (antimicrobial derivatives) [12,13], sirtuin 2-selective inhibitors [14,15], crosscoupling reactions [16,17], and positron emission tomography [18,19], have also been reported, and some reactions have been evaluated in a scale-up fashion [20,21].…”