An Apparent Correlation between the <i>in Vitro</i> Activity of Chloramphenicol Analogs and Electronic Polarizability

Cammarata, Arthur

doi:10.1021/jm00316a004

Cited by 36 publications

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“…These include descriptors containing information on atomic net and partial charges [15]. Descriptors for highest negative and positive charges are also informative, as well as molecular polarizability [16]. Partial negatively or positively charged solvent-accessible atomic surface areas have also been used as informative electrostatic descriptors for modeling intermolecular hydrogen bonding [17].…”

Section: Electrostatic and Quantum-chemical Descriptorsmentioning

confidence: 99%

Computational Methods in Developing Quantitative Structure-Activity Relationships (QSAR): A Review

Dudek¹,

Arodź²,

Gálvez³

2006

CCHTS

365

238

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Virtual filtering and screening of combinatorial libraries have recently gained attention as methods complementing the high-throughput screening and combinatorial chemistry. These chemoinformatic techniques rely heavily on quantitative structure-activity relationship (QSAR) analysis, a field with established methodology and successful history. In this review, we discuss the computational methods for building QSAR models. We start with outlining their usefulness in high-throughput screening and identifying the general scheme of a QSAR model. Following, we focus on the methodologies in constructing three main components of QSAR model, namely the methods for describing the molecular structure of compounds, for selection of informative descriptors and for activity prediction. We present both the well-established methods as well as techniques recently introduced into the QSAR domain.

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Section: Electrostatic and Quantum-chemical Descriptorsmentioning

confidence: 99%

Computational Methods in Developing Quantitative Structure-Activity Relationships (QSAR): A Review

Dudek¹,

Arodź²,

Gálvez³

2006

CCHTS

365

238

View full text Add to dashboard Cite

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“…The ability of the molecule to participate in van der Waals and dispersion interactions depends on polarizability and is also related to hydrophobicity and other biological activities 39,40 .…”

Section: Molecular Polarizability and Hyperpolarizability Analysismentioning

confidence: 99%

Quantum Chemical Investigations on the Structure, Bonding Orbitals, Frontier Molecular Orbitals and Reactivity Properties of Diphenylguanidine ? Vulcanizing Accelerator

2019

Chem Sci Trans

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The molecular structure and reactivity parameters of diphenylguanidine (DPG) were simulated with quantum chemical calculations by using the standard 6-31G**, 6-311++G** and cc-pVDZ basis sets. The bond distance of N1-C2 and N3-C2 are 1.39 Å and 1.42 Å, respectively. The N1-C2 bond posses much more double bond character than the N3-C2 with the longer C-N bond length, though both have partial double-bond character. The molecule exists in the more stable imino form. The C-N bond which connects the aromatic ring has a length of 1.28-1.30 Å, close to that of a typical C=N double bond (ca. 1.28 Å), and is shorter than the other two C-N bonds of the guanidine. The planarity of the tabiliza group is confirmed from the determined bond angles and torsion angles. The N1-C2-N3 bond angle (109.5°) is always smaller than the other two angles (N1-C2-N4 (123.2 o ) and N3-C2-N4 (127.2 o )). The MEP of the molecule spread in the range +1.224e×10 -2 to -1.224e×10 -2 . The range of total electron density of DPG is +5.545e×10 -2 to -5.545e×10 -2 . The bonding orbital for C2−N3 has 38.07% C2 character in a sp 2.24 hybrid and has 61.93% N3 character in a sp 1.94 hybrid orbital. This clearly reveals the partial double bond character of N1-C2 and C2-N3 bonds. The bond pair donor orbital, π CC → π* CC interaction between the phenyl ring carbon atoms are more tabilizat and the tabilization energy of these interactions lie in the range 16.97-22.78 kcal mol -1 . The large total dipole moment of DPG (3.208 D) shows that the polar nature of the molecule. The atoms C2, C13, C22 and C24 are most prone to nucleophilic attack while the electrophilic attack is more on C2, C19 and C12 atoms. The sites C2, C12, C19, C22 and C24 are more susceptible to free radical attack. Fukui dual reactivity descriptor (∆f k ), the dual local softness (∆s k ) and the multiphilicity descriptors (∆ω k ) indicate that the atoms C2, C9, C21 and C22 are more favorable for nucleophilic attack. The atoms N1, N3, C8, C19 and C23 are more favorable for electrophilic attack.

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“…Multiple regression analyses of structure-activity data (Hansch, Muir, Fujita, Maloney, Geiger and Streich, 1963;Cammarata, 1967;Hansch, Kutter and Leo, 1969;Hansch et al, 1973) have focused on resolving the electronic and penetration propertieS-which are conferred upon the chloramphenicol molecule by derivatization. Specifically, this approach was intended to design derivatives "better" than the antibiotic itself (Hansch et al, 1973).…”

Section: Structure-activity Relationships Which Determine Inhibitmentioning

confidence: 99%

“…6) suggest that nitrophenyl is almost 2 kcal/mole more strongly bound than phenyl and these results are consistent with occurrence of a charge-transfer interaction at the active site (review: Shifrin, 1973). There is also a hydrophobic component to the aryl binding, as shown by dependence on log P and polarizability (Hansch et al, 1973;Cammarata, 1967). The benzylic alcohol oxygen is either an analog of a serine hydroxymethyl side chain, or it may impinge on the active site where the free amine of aminoacyl-tRNA is bound to the A-site according to the mechanism of Cheney (1974).…”

Section: Model For Chloramphenicol Inhibition Of Transpeptidationmentioning

confidence: 99%

A Structural Model of the Chloramphenicol Receptor Site

Hahn¹,

Gund²

1975

Drug Receptor Interactions in Antimicrobial Chemotherapy

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I . I NTRODUCTI ONHaving a relatively simple chemical structure, chloramphenicol became the first antibiotic to be synthesized by organic-chemical methods (Controulis, Rebstock and Crooks, 1949). A large number of chloramphenicol derivatives was subsequently prepared. Kolosov, Shemiakin, Khokhlov and Gurevich tabulated, in 1961, more than 500 such compounds, and the total number of known chloramphenicol derivatives is, by now, much greater.For many of these substances, data on their growth-inhibitory potencies for bacteria have been reported. Also, after it was recognized that chloramphenicol acts through specific inhibition of bacterial protein biosynthesis (Hahn and Wisseman, 1951; Gale and Folkes, 1953; Wisseman, Smadel, Hahn and Hopps, 1954) and cell-free model systems of protein synthesis were subsequently developed, chloramphenicol derivatives have been tested for inhibitions of such systems. Hence, the chloramphenicol series of compounds appears to be suited to the derivation of structure-activity relationships.The recent identification of a chloramphenicol binding protein which is a constituent of the 50s subunit of 70s ribosomes (Nierhaus and Nierhaus, 1973;Pongs, Bald and Erdmann, 1973) has renewed our interest in these structureactivity relationships and has encouraged us to analyze them with a view to deriving a structural model of a chloramphenicol receptor site which we infer to be located on the peptidyl transferase which is part of the 50s ribosomal subunit. II. STRUCTURE-ACTIVITY RELATIONSHIPS WHICH DETERMINE INHIBITION OF BACTERIAL GROWTHFirst systematic efforts to derive for chloramphenicol derivatives structureactivity rules for bacterial growth inhibition were made by Hahn (1955), Shemiakin, Kolosov, Levitov, Germanova, Karapetian, Shvetsov and Bamdas (1955, 1956) and Hahn, Hayes, Wisseman, Hopps and Smadel (1956). Both groups of workers arrived independently at the same conclusions; reviews of these conclusions represented the state of the art for several years (Kolosov et al., 1961;Hahn, 1967a). Both groups also called attention to the fact that data-on growth inhibitions by chloramphenicol derivatives had been obtained in many laboratories using varieties of methods and test organisms and could not be considered to be better than semi-quantitative approximations which did not lend themselves to the derivation of quantitative structure-activity relationships.

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An Apparent Correlation between the in Vitro Activity of Chloramphenicol Analogs and Electronic Polarizability

Cited by 36 publications

References 0 publications

Computational Methods in Developing Quantitative Structure-Activity Relationships (QSAR): A Review

Computational Methods in Developing Quantitative Structure-Activity Relationships (QSAR): A Review

Quantum Chemical Investigations on the Structure, Bonding Orbitals, Frontier Molecular Orbitals and Reactivity Properties of Diphenylguanidine ? Vulcanizing Accelerator

A Structural Model of the Chloramphenicol Receptor Site

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