4,4'-Dichloro-2,2'-iminodibenzoic Acid

Armas, Héctor Novoa de; Hernández, R. Pomés; Rodríguez, Julio Duque; Toscano, Rubén A.

doi:10.1107/s0108270195008572

Cited by 4 publications

(3 citation statements)

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“…When bound to Mtb ‐AnPRT, both carboxylate groups of ACS172 are orientated on one side of the molecule and form hydrogen bonds with the arginine and asparagine residues (Arg194, Arg193, Asn138) that line one side of the substrate‐binding tunnel of Mtb ‐AnPRT (Figure 4 A). The presence of a hydrogen bond within ACS172 is consistent with crystallographic data for 7 (an analogue of LBZ) and mefenamic acid ( 8 ), a nonsteroidal anti‐inflammatory drug (NSAID, Figure 4 B), which show intramolecular hydrogen bonds between their amino and carboxylate groups 25c. 26…”

Section: Resultssupporting

confidence: 75%

Repurposing the Chemical Scaffold of the Anti‐Arthritic Drug Lobenzarit to Target Tryptophan Biosynthesis in Mycobacterium tuberculosis

et al. 2014

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The emergence of extensively drug-resistant strains of Mycobacterium tuberculosis (Mtb) highlights the need for new therapeutics to treat tuberculosis. We are attempting to fast-track a targeted approach to drug design by generating analogues of a validated hit from molecular library screening that shares its chemical scaffold with a current therapeutic, the anti-arthritic drug Lobenzarit (LBZ). Our target, anthranilate phosphoribosyltransferase (AnPRT), is an enzyme from the tryptophan biosynthetic pathway in Mtb. A bifurcated hydrogen bond was found to be a key feature of the LBZ-like chemical scaffold and critical for enzyme inhibition. We have determined crystal structures of compounds in complex with the enzyme that indicate that the bifurcated hydrogen bond assists in orientating compounds in the correct conformation to interact with key residues in the substrate-binding tunnel of Mtb-AnPRT. Characterising the inhibitory potency of the hit and its analogues in different ways proved useful, due to the multiple substrates and substrate binding sites of this enzyme. Binding in a site other than the catalytic site was found to be associated with partial inhibition. An analogue, 2-(2-5-methylcarboxyphenylamino)-3-methylbenzoic acid, that bound at the catalytic site and caused complete, rather than partial, inhibition of enzyme activity was found. Therefore, we designed and synthesised an extended version of the scaffold on the basis of this observation. The resultant compound, 2,6-bis-(2-carboxyphenylamino)benzoate, is a 40-fold more potent inhibitor of the enzyme than the original hit and provides direction for further structure-based drug design.

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Section: Resultssupporting

confidence: 75%

Repurposing the Chemical Scaffold of the Anti‐Arthritic Drug Lobenzarit to Target Tryptophan Biosynthesis in Mycobacterium tuberculosis

et al. 2014

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“…A representative example of Cl(lp)-p interactions is illustrated by the crystal structure of a very simple molecule, namely bis(4,4 0 -dichloro-2,2 0 -iminodibenzoic acid) (CSD refcode ZIVKIY), 30 whose schematic representation is shown in Fig. 8.…”

Section: Resultsmentioning

confidence: 99%

Lone pair–π interactions: a new supramolecular bond?

2008

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“…31,32 A few examples of lp-p interactions involving synthetic molecules have been reported so far in the literature. [33][34][35] The arrangement of the H-and T-shaped supramolecules in the crystal is mainly determined by the p-p interactions between the aromatic Pc(2-) macrorings. The H-shaped molecules are arranged in a back-to-back fashion forming stacks running along the [100] direction with a distance of 3.349 (3) A between the N 4planes of Pc(2-) macrorings (Fig.…”

Section: Synthesis and Equilibrium In Solutionmentioning

confidence: 99%