Short Communication Anti-HIV agents: design and discovery of new potent RT inhibitors Maria Letizia Barreca a , Alba Chimirri a , Erik De Clercq b , Laura De Luca a , Anna-Maria Monforte a, *, Pietro Monforte a , Angela Rao a , Maria Zappala ` a a Dipartimento Farmaco-Chimico, Universita ` degli Studi di Messina, Viale Annunziata, 98168 Messina, Italy b Rega Institute for Medical Research, Katholieke Universiteit Leuven, 10 Minderbroedersstraat, 3000 Leuven, Belgium Accepted 4 July 2002 Abstract This paper reports our work in the field of nonnucleoside RT inhibitors (NNRTIs). On the basis of extensive studies on 1H ,3H - thiazolo[3,4-a ]benzimidazole derivatives (TBZs) followed by structure  /activity relationship (SAR) considerations and molecular modeling, the design and synthesis of a series of 2,3-diaryl-1,3-thiazolidin-4-ones have been performed. Some derivatives proved to be highly effective in inhibiting human immunodeficiency virus type-1 (HIV-1) replication at nanomolar concentrations with minimal toxicity, acting as reverse transcriptase (RT) inhibitors. Computational studies were used in order to probe the binding of our ligands to HIV-1-RT. # 2003 E ´ ditions scientifiques et me ´dicales Elsevier SAS. All rights reserved. Keywords: NNRTIs; anti-HIV agents; 2,3-Diaryl-1,3-thiazolidin-4-ones Reverse transcriptase (RT) is a key enzyme which plays an essential and multifunctional role in the replication of the human immunodeficiency virus type- 1 (HIV-1) and thus constitutes an attractive target for the development of new drugs useful in AIDS therapy [1]. The first antiretroviral drugs approved in the USA and Europe were nucleoside RT inhibitors (NRTIs) which compete with normal nucleoside substrates for incorporation into the viral genome, thus behaving as chain terminators [2]. Unlike nucleoside analogues, nonnucleoside RT in- hibitors (NNRTIs) bind in a noncompetitive manner to a specific ‘pocket’ of the HIV-1 RT altering its ability to function [3,4]. X-ray crystallographic studies of NNRTI  /RT com- plexes have shown that the NNRTIs present a very similar conformational ‘butterfly-like’ shape and appear to function as p-electron donors to aromatic side-chain residues surrounding the binding pocket [5]. Presently, three NNRTIs namely nevirapine, dela vir- dine and efavirenz are available in clinical practice. Combination of these drugs with NRTIs and protease inhibitors (PIs) leads to a dramatic decrease of the viral load in most of the HIV-infected patients. However, in view of the increasing incidence of resistance to current drug regimens and the frequency of adverse events, the development of novel antiviral agents, also effective against mutant HIV strains, remains a high priority for medical research. In previous papers [6,7] we reported the synthesis and biological activity of a series of 1-aryl-1H ,3H -thia- zolo[3,4-a ]benzimidazoles (TBZs) highly active as HIV-1 NNRTIs. We demonstrated that, analogously to other NNRTIs, their biological activity was associated with the possibility of assuming a ‘butterfly-like’ shape that allows the interactions between the aromatic groups of TBZs and aminoacid residues in the non-nucleoside inhibitor binding pocket (NNIBP) of RT [8]. The lead compound of this class, 1-(2,6-difluorophe- nyl)-1H ,3H -thiazolo[3,4-a ]benzimidazole (TBZ, NSC 625487), proved to be a highly potent inhibitor of HIV-1 induced cytopathic effect; it inhibited the replica- tion of various strains of HIV-1, including a zidovudine- resistant strain (G910-6), in a variety of human cell lines [8]. In addition, combination of TBZ with either * Correspondence and reprints. E-mail address: monforte@pharma.unime.it (A.-M. Monforte). Il Farmaco 58 (2003) 259  /263 www.elsevier.com/locate/farmac 0014-827X/03/$ - see front matter # 2003 E ´ ditions scientifiques et me ´dicales Elsevier SAS. All rights reserved. doi:10.1016/S0014-827X(03)00024-7