Benzazaborinines as Novel Bioisosteric Replacements of Naphthalene: Propranolol as an Example

Rombouts, Frederik; Tovar, Fulgencio; Austin, Nigel; Tresadern, Gary; Trabanco, Andrés A.

doi:10.1021/acs.jmedchem.5b01088

Cited by 72 publications

(46 citation statements)

References 35 publications

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“…9 More recently, BN isosteres of naphthalene have been profiled in vitro and in vivo in terms of biological activity and ADME (absorption, distribution, metabolism, excretion) properties. 10,11 …”

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confidence: 99%

Hydrogen Bonding of 1,2-Azaborines in the Binding Cavity of T4 Lysozyme Mutants: Structures and Thermodynamics

et al. 2016

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Protein crystallography and calorimetry were used to characterize the binding of 1,2-azaborines to model cavities in T4 lysozyme in direct comparison to their carbonaceous counterparts. In the apolar L99A cavity, affinity for Ab dropped only slightly versus benzene. In the cavity designed to accommodate a single hydrogen bond (L99A/M102Q), Gln102=O⋯H—N hydrogen bonding for Ab and BEtAb was observed in the crystallographic complexes. The strength of the hydrogen bonding was estimated as 0.94 and 0.64 kcal/mol for Ab and BEtAb, respectively. This work unambiguously demonstrates that 1,2-azaborines can be readily accommodated in classic aryl recognition pockets and establishes one of 1,2-azaborine’s distinguishing features from its carbonaceous isostere benzene: its ability to serve as an NH hydrogen bond donor in a biological setting.

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confidence: 99%

Hydrogen Bonding of 1,2-Azaborines in the Binding Cavity of T4 Lysozyme Mutants: Structures and Thermodynamics

et al. 2016

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“…NBO calculations show that the HOMO of PBaz 3 has 64 %pcharacter which is significantly more than the 54 %for PPh 3 ; the greater p-character is also apparent from the shapes of the HOMO orbitals (Figure 3c). [46] The 31 Pa nd 11 BNMR signals for the Baz 3 P·BH 3 are at d P = À171 and d B = À42 ppm which correspond to coordination chemical shifts of Dd P =+34 and Dd B = À41 ppm;t hese values are similar to those for Ph 3 P·BH 3 (Dd P =+26 and Dd B = À38 ppm). [45] Reaction of PBaz 3 with BH 3 .A ddition of H 3 B·THF to PBaz 3 generated ap roduct that has been characterised in solution by 31 Pa nd 11 BNMR spectroscopy and assigned the structure Baz 3 P·BH 3 (Scheme 2);t he analogous Ph 3 P·BH 3 is formed similarly from H 3 B·THF and PPh 3 .…”

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confidence: 66%

Inorganic Triphenylphosphine

et al. 2018

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Ac ompletely inorganic version of one of the most famous organophosphorus compounds,t riphenylphosphine, has been prepared. Ac omparison of the crystal structures of inorganic triphenylphosphine,P Baz 3 (where Baz = B 3 H 2 N 3 H 3 )a nd PPh 3 shows that they have superficial similarities and furthermore,t he Lewis basicities of the two compounds are remarkably similar.H owever,t heir oxygenation and hydrolysis reactions are starkly different. PBaz 3 reacts quantitatively with water to give PH 3 and with the oxidizing agent ONMe 3 to give the triply-O-inserted product P(OBaz) 3 ,a ni norganic version of triphenyl phosphite; ac orresponding transformation with PPh 3 is inconceivable. Thermodynamically,w hat drives these striking differences in the chemistry of PBaz 3 and PPh 3 is the great strength of the B À Ob ond.

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“…The concept of bioisosteric replacements has proven to be one of the successful and fruitful methods for solving problems of this type [1,2]. By now it has become a powerful tool for purposeful synthesis of biologically active substances not only with the desired pharmacological activity, but with improved characteristics compared to the structures-prototypes [3,4,5,6,7,8,9]. …”

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confidence: 99%

New Synthesis, Structure and Analgesic Properties of Methyl 1-R-4-Methyl-2,2-Dioxo-1H-2λ6,1-Benzothiazine-3-Carboxylates

et al. 2017

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According to the principles of the methodology of bioisosteric replacements a series of methyl 1-R-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylates has been obtained as potential analgesics. In addition, a fundamentally new strategy for the synthesis of compounds of this chemical class involving the introduction of N-alkyl substituent at the final stage in 2,1-benzothiazine nucleus already formed has been proposed. Using nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry and X-ray diffraction analysis it has been proven that in the DMSO/K2CO3 system the reaction of methyl 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate and alkyl halides leads to formation of N-substituted derivatives with good yields regardless of the structure of the alkylating agent. The peculiarities of NMR (1Н and 13С) spectra of the compounds synthesized, their mass spectrometric behavior and the spatial structure are discussed. In N-benzyl derivative the ability to form a monosolvate with methanol has been found. According to the results of the pharmacological testing conducted on the model of the thermal tail-flick it has been determined that replacement of 4-ОН-group in methyl 1-R-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylates for the methyl group is actually bioisosteric since all methyl 1-R-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylates synthesized demonstrated a statistically significant analgesic effect. The majority of the substances can inhibit the thermal pain response much more effective than piroxicam in the same dose. Under the same conditions as an analgesic the N-methyl-substituted analog exceeds not only piroxicam, but more active meloxicam as well. Therefore, it deserves in-depth biological studies on other experimental models.

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Benzazaborinines as Novel Bioisosteric Replacements of Naphthalene: Propranolol as an Example

Cited by 72 publications

References 35 publications

Hydrogen Bonding of 1,2-Azaborines in the Binding Cavity of T4 Lysozyme Mutants: Structures and Thermodynamics

Hydrogen Bonding of 1,2-Azaborines in the Binding Cavity of T4 Lysozyme Mutants: Structures and Thermodynamics

Inorganic Triphenylphosphine

New Synthesis, Structure and Analgesic Properties of Methyl 1-R-4-Methyl-2,2-Dioxo-1H-2λ6,1-Benzothiazine-3-Carboxylates

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