2-chlorovinyl tellurium dihalides, (p-tol)Te[C(H)=C(Cl)Ph]X2 for X = Cl, Br and I: variable coordination environments, supramolecular structures and docking studies in cathepsin B

Abstract

Os estudos cristalográficos mostram que o poliedro de coordenação ao redor do átomo de Te, em cada um dos compostos (p-tol)Te[C(H)=C(Cl)Ph]X 2 , com X = Cl (1), Br (2) e I (3), é uma Ψ-bipirâmide pentagonal distorcida. O grupo vinil em (1) adota uma configuração E o que impede a formação de uma interação intramolecular Te … Cl e em seu lugar é encontrada uma interação intramolecular Te … p. O poliedro de coordenação é formado por um arranjo linear Cl-Te-Cl com o plano pentagonal definido por dois átomos de C dos substituintes orgânicos, um contato intermolecular Te … Cl, uma interação Te … p e um par isolado de elétrons estereoquimicamente ativo. Geometrias de coordenação semelhantes são encontradas para as estruturas com X = Br (2) e I (3), mas a interação p é substituída por uma interação intramolecular Te … Cl devido à adoção de uma configuração Z em torno da ligação vinil. As diferenças nas estruturas são facilmente explicadas em termos de efeitos eletrônicos. Estudos de docking em catepsina B com (1')-(3'), ou seja, compostos 1 a 3 em que há um haleto a menos ligado ao átomo de Te, mostram que há uma ligação eficiente com a proteína pela formação da ligação covalente Te-S Cys29 com a estabilização proporcionada por uma combinação de interações N-H … p, C-H … p e Cl vinyl … H. Estes resultados são comparáveis aos obtidos com inibidores conhecidos da catepsina B o que sugere que os compostos estudados têm potencial atividade biológica.Crystallography shows that the Te atom in each of (p-tol)Te[C(H)=C(Cl)Ph]X 2 , for X = Cl (1), Br (2) and I (3), is within a distorted Ψ-pentagonal bipyramidal geometry. An E configuration for the vinyl group in (1) precludes the formation of an intramolecular Te … Cl interaction so that an intramolecular Te … p interaction is found instead. The coordination environment features a linear Cl-Te-Cl arrangement with the pentagonal plane defined by the two C atoms of the organic substituents, an intermolecular Te … Cl contact, a Te … p interaction and a stereochemically active lone pair of electrons. In the X = Br (2) and I (3) structures, similar coordination geometries are found but the Te … p contact is replaced by an intramolecular Te … Cl contact owing to the adoption of a Z configuration about the vinyl bond. The differences in structure are readily explained in terms of electronic effects. Docking studies of cathepsin B with (1')-(3'), i.e. 1-3 less one Te-bound halide, show efficient binding through the agency of covalent Te-S Cys29 bonds with stabilization afforded by a combination of N-H … p, C-H … p and Cl vinyl … H interactions. These results comparable favorably with known inhibitors of cathepsin B suggesting the title compounds have potential biological activity.Keywords: organotellurium-dihalides, docking studies, cathepsin B, crystal structures, supramolecular arrangements 2-Chlorovinyl Tellurium Dihalides, (p-tol)Te[C(H)=C(Cl)Ph]X 2 for X = Cl, Br and I J. Braz. Chem. Soc. 2156 IntroductionOrganotellurium halides comprise an interesting class of compounds owing...

Crystallographic, DFT and docking (cathepsin B) studies on an organotellurium(IV) compound

“…. Moreover, the same value was found in the crystal structure of the sarcosine oxidase complex with a tellurium compound [47] and in related docking studies [14,38].…”

“…dichloro-(2-chloro-phenylvinyl)-4-methoxyphenyltellurium(IV) (3 in Fig. 1), was performed to understand the inhibition mechanism [14].…”

Crystallographic and docking (Cathepsins B, K, L and S) studies on bioactive halotelluroxetanes

“…With the aim to understand how potential therapeutic agents based on tellurium inhibit cysteine proteases, significant effort has been made to elucidate their binding modes and correlate them with inhibitory data [47][48][49][50][51]. Continuing this research, the present work targets to explain trends in previous published inhibitory data of a series of halotelluroxetanes, Figure 1, against Cathepsins B, K, L and S. New crystallographic data are presented for 1 and 4, Figure 1, and docking studies of cationic ligands 1ꞌ-4ꞌ, i.e.…”

“…The inhibition occurs due to the formation of a Te(IV)-SG covalent bond between the electrophilic tellurium(IV) centre and the nucleophilic thiol group of the catalytic cysteine via the loss of a leaving group bound to the tellurium atom [31,32,47,48]. According to previous work [47,48], to create an environment to satisfy the covalent complex hypothesis, the telluriumbound halide, considered the best leaving group in each of 1-4, was removed giving the corresponding cations 1ꞌ, 2ꞌ, 3ꞌ and 4ꞌ, respectively and these were used to simulate the formation of the Cathepsin-telluroxetane complexes in the enzymes listed in Table 3. It should be noted that after removing the tellurium-bonded halide 3ꞌ is equivalent to 4ꞌ so only 3ꞌ was used for the final stages of the docking studies, i.e.…”

“…As indicated in Table 4, a good and specific Cathepsin B inhibitor should occupy the S1' and S2' sub-sites, especially the S2' sub-site which comprises the occluding loop that was shown to be very important for inhibition activity [48,75]. The docking results, shown in Figure 7 for 2ꞌ and 3ꞌ in Cathepsin B indicate that these do not occupy the S2' sub-site and this may explain the fact of their very low binding affinity values for this protease, as indicated in Table 7.…”