The carboxanilides are nonnucleoside inhibitors (NNIs) of HIV-1 reverse transcriptase (RT), of potential clinical importance. The compounds differ in potency and in their retention of potency in the face of drug resistance mutations. Whereas UC-84, the prototype compound, only weakly inhibits many RTs bearing single point resistance mutations, inhibition by UC-781 is little affected. It has been proposed that UC-38 and UC-781 may form quaternary complexes with RT at a site other than the known binding pocket of other NNIs. X-ray crystal structures of four HIV-1 RT-carboxanilide complexes (UC-10, UC-38, UC-84, and UC-781) reported here reveal that all four inhibitors bind in the usual NNI site, forming binary 1:1 complexes with RT in the absence of substrates with the amide/thioamide bond in cis conformations. For all four complexes the anilide rings of the inhibitors overlap aromatic rings of many other NNIs bound to RT. In contrast, the second rings of UC-10, UC-84, and UC-781 do not bind in equivalent positions to those of other "two-ring" NNIs such as alpha-APA or HEPT derivatives. The binding modes most closely resemble that of the structurally dissimilar NNI, Cl-TIBO, with a common hydrogen bond between each carboxanilide NH- group and the main-chain carbonyl oxygen of Lys101. The binding modes differ slightly between the UC-10/UC-781 and UC-38/UC-84 pairs of compounds, apparently related to the shorter isopropylmethanoyl substituents of the anilide rings of UC-38/UC-84, which draws these rings closer to residues Tyr181 and Tyr188. This in turn explains the differences in the effect of mutated residues on the binding of these compounds.

01 May 1997·Biochemical and Biophysical Research CommunicationsQ3 · BIOLOGY

Models Which Explain the Inhibition of Reverse Transcriptase by HIV-1-Specific (Thio)carboxanilide Derivatives1

Q3 · BIOLOGY

Article

Author: D I Stuart ; R M Esnouf ; E Schwartz ; E De Clercq ; J Balzarini

The (thio)carboxanilide derivatives are potent and selective inhibitors of HIV-1 reverse transcriptase (RT) and have a favourable antiviral activity spectrum. To understand better their mode of action, and to provide a structural basis for further improvement, models of RT complexed with four (thio)carboxanilide inhibitors (UC781, UC10, UC38 and UC84) have been constructed based on the X-ray structure of RT complexed with 9-chloro-TIBO. In the models, the protein conformation is similar to that of the RT-TIBO complex and the complexes are stabilised by hydrogen bonding between the inhibitors and the main chain oxygen of Lys101. Significant hydrophobic interactions include those with Leu100, Val106, Val179, Tyr188, Phe227, Leu234, and His235. The thiocarboxanilides UC781 and UC10 also make important hydrophobic interactions with Trp229. The models are consistent with the inhibitors' relative antiviral potencies and the observed resistance data. They further predict that mutations to Phe227, Trp229, or Leu234 might confer resistance. Since these are not observed, some constraining structural or functional role for these residues in the active enzyme is suggested.

01 Aug 1996·Molecular pharmacology

Highly favorable antiviral activity and resistance profile of the novel thiocarboxanilide pentenyloxy ether derivatives UC-781 and UC-82 as inhibitors of human immunodeficiency virus type 1 replication.

Article

Author: Witvrouw, M ; Balzarini, J ; Perno, C F ; Pelemans, H ; Aquaro, S ; Schols, D ; De Clercq, E ; Karlsson, A

The novel human immunodeficiency virus type 1-specific thiocarboxanilide derivatives that contain either a substituted furanyl (UC-781) or thienyl (UC-82) ring linked to the thiocarboxy group and a pentenyloxyether chain linked to the 4-chlorophenyl ring in meta position show highly favorable antiviral properties. Compounds UC-781 and UC-82 discovered by scientists at Uniroyal Chemical Ltd. proved to be > or = 5-10-fold more inhibitory to wild-type human immunodeficiency virus type 1 strains (EC50 approximately 0.002 microgram/ml) than the thiocarboxanilide oxime ether UC-10 and other non-nucleoside reverse transcriptase inhibitors such as nevirapine, bis(heteroaryl)piperazine, and tetrahydroimidazo[4,5,l-jk][1,4]-benzodiazepin-2(1H)-one. In addition, the compounds were able to knock out virus replication in cell culture at concentrations that were 20-50-fold lower than those of nevirapine or bis(heteroaryl)piperazine. They were also highly efficient (EC50 < or = 0.02 microgram/ml) in suppressing the replication of mutant virus strains that contained mutations in their reverse transcriptase that conferred resistance to other non-nucleoside reverse transcriptase inhibitors (i.e., Tyr181 to Cys, Lys103 to Asn, Val106 to Ala, and Leu100 to Ile). The compounds selected for virus mutants that were only marginally resistant to the thiocarboxanilides ( < 10-20-fold). The antiviral activity of the compounds was only slightly affected by the presence of high concentrations of human serum, and the compounds were shown to be highly stable in the presence of human serum for at least 24 hr at room temperature.

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Indication	Highest Phase	Country/Location	Organization	Date
HIV Infections	Preclinical	US	biosyn Corp.	-
HIV Infections	Preclinical	US	The Aaron Diamond AIDS Research Center	-

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