Crystal polymorphism is encountered in all areas of research involving solid substances. Its occurrence introduces complications during manufacturing processes and adds another dimension to the complexity of designing materials with specific properties. Research on polymorphism is fraught with unique difficulties due to the subtlety of polymorphic transformations and the inadvertent formation of pseudopolymorphs. In this report, a summary of thermodynamic, kinetic and structural considerations of polymorphism is presented. A wide variety of techniques appropriate to the study of organic crystalline polymorphism and pseu-dopolymorphism is then surveyed, ranging from simple crystal density measurement to observation of polymorphic transformations using variable-temperature synchrotron X-ray diffraction methods. Application of newer methodology described in this report is yielding fresh insights into the nature of the crystallization process, holding promise for a deeper understanding of the phenomenon of polymorphism and its practical control.

Crystalline Polymorphism of Organic Compounds

For many years, DNA gyrase was thought to be responsible both for unlinking replicated daughter chromosomes and for controlling negative superhelical tension in bacterial DNA. However, in 1990 a homolog of gyrase, topoisomerase IV, that had a potent decatenating activity was discovered. It is now clear that topoisomerase IV, rather than gyrase, is responsible for decatenation of interlinked chromosomes. Moreover, topoisomerase IV is a target of the 4-quinolones, antibacterial agents that had previously been thought to target only gyrase. The key event in quinolone action is reversible trapping of gyrase-DNA and topoisomerase IV-DNA complexes. Complex formation with gyrase is followed by a rapid, reversible inhibition of DNA synthesis, cessation of growth, and induction of the SOS response. At higher drug concentrations, cell death occurs as double-strand DNA breaks are released from trapped gyrase and/or topoisomerase IV complexes. Repair of quinolone-induced DNA damage occurs largely via recombination pathways. In many gram-negative bacteria, resistance to moderate levels of quinolone arises from mutation of the gyrase A protein and resistance to high levels of quinolone arises from mutation of a second gyrase and/or topoisomerase IV site. For some gram-positive bacteria, the situation is reversed: primary resistance occurs through changes in topoisomerase IV while gyrase changes give additional resistance. Gyrase is also trapped on DNA by lethal gene products of certain large, low-copy-number plasmids. Thus, quinolone-topoisomerase biology is providing a model for understanding aspects of host-parasite interactions and providing ways to investigate manipulation of the bacterial chromosome by topoisomerases.

DNA gyrase, topoisomerase IV, and the 4-quinolones.

The interactions of metal ions with quinolone antibacterial agents

We have proposed a cooperative quinolone-DNA binding model for the inhibition of DNA gyrase. The essential feature of the model is that bound gyrase induces a specific quinolone binding site in the relaxed DNA substrate in the presence of ATP. The binding affinity and specificity are derived from two unique and equally important functional features: the specific conformation of the proposed single-stranded DNA pocket induced by the enzyme and the unique self-association phenomenon (from which the cooperativity is derived) of the drug molecules to fit the binding pocket with a high degree of flexibility. Supporting evidence for and implications of this model are provided.

Mechanism of inhibition of DNA gyrase by quinolone antibacterials: a cooperative drug--DNA binding model.

Structures of Five Antibiotics Bound at the Peptidyl Transferase Center of the Large Ribosomal Subunit

The structure of sulfamerazine, C11H12N4O2S, a very important sulfonamide drug, has been solved by direct methods with X-ray diffraction data collected using CuKα radiation. The crystals are orthorhombic, witha=9.145(1),b=11.704(1),c=22.884(2) A and space groupPbca. The structure was refined with 2082 observed independent reflections, measured on a CAD-4 diffractometer, to a finalR value of 0.078. The molecule has similar conformational features to those observed in other sulfonamide drugs.

Crystal structure of sulfamerazine

Refinement of the structure of nalidixic acid

The structure of chloramphenicol, C11H12Cl2N2O5, an important broad-​spectrum antibiotic, was solved by direct methods and refined by Fourier and least-​squares to a R of 0.069. The crystals are orthorhombic, space group C2221, with a 7.335(3)​, b 17.552(8)​, and c 22.159(6) A; d.(calcd.) = 1.50 and d.(obsd.) = 1.49 for Z = 8. The side chain exists in the 'alicyclic' form, stabilized by H bonding between the hydroxyl groups. The dichloroacetamido moiety is folded back over the Ph ring.

/pdf/the-structure-of-chloramphenicol-42a766khc3.pdf

The structure of chloramphenicol

C s H 6 N 8 0 4 , M r = 278.2, monoclinic, P21/n, Z = 4, T = 293 K, a = 10.991 (2), b = 9.056 (2), c = 11.706(2)A, f l = 101.50(1) ° , V = 1141.8A3, D m = 1.60, D x 1.62 Mg m 3 , g 0.118 mm -~, C u K a radiation (2 -1.54051 A). Final R = 0.049 for 1228 independent reflections. The title compound, DBTYH, consists of a 2,4-dinitrobenzaldehyde moiety and a tetrazole moiety bridged by a hydrazone chain. Each molecule is hydrogen-bonded to three other molecules through four hydrogen-bond linkages (two acceptor and two donor) centered on the tetrazole ring. The entire molecule is approximately planar with the exception of one nitro group which is rotated 39 ° out of the plane of the benzene ring and has a short C H . . . O distance that could indicate a weak intramolecular hydrogen bond. The crystal was automatically recentered every 428 reflections, with four standard reflections checked after each 102 measurements. Of the resulting 1701 independent reflections, 1228 reflections with F > 3a(F) were used in the refinement. Lorentz-polarization corrections were applied; decay and absorption corrections were not necessary. The structure was solved with MULTAN (Declercq, Germain, Main & Woolfson, 1973) using 141 reflections (Emi n = 1.75) and three general phase relationships. All but one of the non-H atoms were located in Table 1. Fractional coordinates (x 104, for H x 103) and Beq or Bis o (A 2) with e.s.d.'s in parentheses, and deviations (A × 10 a A) of non-hydrogen atoms from the least-squares plane (see text) Introduetlon. DBTYH, which was prepared by reacting (1H-tetrazol-5-yl)hydrazine with 2,4-dinitrobenzaldehyde (Thiele, 1898), has been used in the preparation of explosives (Jaffery, 1976) as have other tetrazole x compounds (Duke, 1971; Bryden, 1958). Its thermal o ( 1 ) -1246(6) decomposition has been studied under dynamic and o(2) 34 (7) o(3) 850 (8) isothermal conditions using a differential scanning o(4) 1770(7) calorimeter (Om Reddy, Krishna Mohan, Mohan N ( 1 ) 2158(6) N(2) 2490 (7) Murali & Chatterjee, 1981). N(3) 1856 (6) Oscillation and Weissenberg photographs of a yellow N(4) 1128 (6) N(5) 807 (6) crystal of DBTYH (grown by slow evaporation from a N(6) 1127 (6) 2:1 methanol-dioxane mixture) showed the crystal N ( 7 ) -359(6) system to be monoclinic, with systematic absences 0k0, N(8) 1249 (7) C(1) 818 (7) k = 2n + 1 and hOl, h + l = 2n + 1, indicating space c(2) 325 (7) group P21/n, with general positions x,y,z and 1⁄2 x, 1⁄2 + c(3) 450 (7) y, 1⁄2 -z. The crystal density was measured by flotation c(4) 1113 (7) C(5) 1649 (8) using iodobenzene and kerosene, c(6) 1484 (8) Accurate unit-cell parameters were obtained by c(7) 614(7) least-squares refinement of 15 carefully centered c(8) 1341(7) H(N1) 247 (8) reflections and 1952 reflections (20ma x : 120 °) were H(N5) 36(9) measured using the 0-20 scan mode on a Syntex P21H(C3) 7 (6) F diffractometer (crystal size 0.06 x 0.09 x 0.11 mm). H(C5) 214 (7) H(C6) 186 (6) H(C7) 0 (5) * Permanent address: Depar tment of Physics, Central College, Bangalore University, Bangalore 560 001, India. 0567-7408/82/092487-04501.00 Beq or

http://journals.iucr.org/b/issues/1982/09/00/a21494/a21494.pdf

2,4-Dinitrobenzaldehyde (1H-tetrazol-5-yl)hydrazone

Experimental The structure of chloramphenicol, D-(--)-threo-2,2dichloro-N- [ fl-hy drox y-ct- (hy droxy methyl)-p- nitrophenethyl]acetamide, C l~Hx2C12N2Os, an important broadspectrum antibiotic, has been solved by direct methods with X-ray diffraction data collected using Mo Ka radiation. The crystals are orthorhombic, a = 7.335 (3), b = 17.552 (8), c = 22.159 (6) A, with space group C222~, and the structure has been refined by Fourier and least-squares techniques to an R of 0.069 for 940 observed reflections. The side chain exists in the 'alicyclic' form, stabilized by hydrogen bonding between the hydroxyl groups. The dichloroacetamido moiety is folded back over the phenyl ring.

K. Ravindra Acharya

Papers

Crystal structure of sulfamerazine

Refinement of the structure of nalidixic acid

The structure of chloramphenicol

2,4-Dinitrobenzaldehyde (1H-tetrazol-5-yl)hydrazone

The Structure of Chloramphenieol