Planarity of heteroaryldithiocarbazic acid derivatives showing tuberculostatic activity. II. Crystal structures of 3-[amino(pyrazin-2-yl)methylidene]-2-methylcarbazic acid esters.

Four compounds showing moderate antituberculostatic activity have been studied to test the hypothesis that the planarity of the 2-[amino(pyrazin-2-yl)methylidene]dithiocarbazate fragment is crucial for activity. N'-Anilinopyrazine-2-carboximidamide, C(11)H(11)N(5), D1, and diethyl 2,2'-[({[amino(pyrazin-2-yl)methylidene]hydrazinylidene}methylidene)bis(sulfanediyl)]diacetate, C(14)H(19)N(5)O(4)S(2), B1, maintain planarity due to conjugation and attractive intramolecular hydrogen-bond contacts, while methyl 3-[amino(pyrazin-2-yl)methylidene]-2-methyldithiocarbazate, C(8)H(11)N(5)S(2), C1, and benzyl 3-[amino(pyrazin-2-yl)methylidene]-2-methyldithiocarbazate, C(14)H(15)N(5)S(2), C2, are not planar, due to methylation at one of the N atoms of the central N-N bond. The resulting twists of the two molecular halves (parts) of C1 and C2 are indicated by torsion angles of 116.5 (2) and -135.9 (2)°, respectively, compared with values of about 180° in the crystal structures of nonsubstituted compounds. As the methylated derivatives show similar activity against Mycobacterium tuberculosis to that of the nonsubstituted derivatives, maintaining planarity does not seem to be a prerequisite for activity.

Planarity of heteroaryldithiocarbazic acid derivatives showing tuberculostatic activity. III. Mono- and diesters of 3-(pyrazin-2-ylcarbonyl)dithiocarbazic acid.

Methyl 2-(pyrazin-2-ylcarbonyl)hydrazinecarbodithioate, C(7)H(8)N(4)OS(2), (E1), N'-[bis(methylsulfanyl)methylidene]pyrazine-2-carbohydrazide, C(8)H(10)N(4)OS(2), (F1), N'-[bis(methylsulfanyl)methylidene]-6-methoxypyrazine-2-carbohydrazide, C(9)H(12)N(4)O(2)S(2), (F2), and methyl 1-methyl-2-(pyrazin-2-ylcarbonyl)hydrazinecarbodithioate, C(8)H(10)N(4)OS(2), (G1), can be considered as derivatives of classical (thio)amide-type tuberculostatics, and all are moderately active against Mycobacterium tuberculosis. This study was undertaken in a search for relationships between activity and specific intramolecular interactions, especially conjugations and hydrogen-bond contacts, and the molecular structures were compared with respective amine analogues, also active against the pathogen. Despite the differences between the amine and carbonyl groups with opposite functions in the hydrogen bond, the two types of structure show a surprisingly similar planar geometry, mostly due to the conjugations aided by the bifurcated intramolecular hydrogen-bond contact between the N-H group of the central hydrazide group as donor and a pyrazine N atom and an S atom of the dithio function as acceptors. Planarity was suggested to be crucial for the tuberculostatic activity of these compounds. The N-methylated derivative (G1) showed a significant twist at the N-N bond [torsion angle = -121.9 (3)°] due to the methyl substitution, which precludes an intramolecular N-H···S contact and the planarity of the whole molecule. Nonetheless, the compound shows moderate tuberculostatic activity.

Planarity of heteroaryldithiocarbazic acid derivatives showing tuberculostatic activity: structure-activity relationships.

The search for new tuberculostatics is an important issue due to the increasing resistance of Mycobacterium tuberculosis to existing agents and the resulting spread of the pathogen. Heteroaryldithiocarbazic acid derivatives have shown potential tuberculostatic activity and investigations of the structural aspects of these compounds are thus of interest. Three new examples have been synthesized. The structure of methyl 2-[amino(pyridin-3-yl)methylidene]hydrazinecarbodithioate, C8H10N4S2, at 293 K has monoclinic (P21/n) symmetry. It is of interest with respect to antibacterial properties. The structure displays N-H...N and N-H...S hydrogen bonding. The structure of N'-(pyrrolidine-1-carbonothioyl)picolinohydrazonamide, C11H15N5S, at 100 K has monoclinic (P21/n) symmetry and is also of interest with respect to antibacterial properties. The structure displays N-H...S hydrogen bonding. The structure of (Z)-methyl 2-[amino(pyridin-2-yl)methylidene]-1-methylhydrazinecarbodithioate, C9H13N4S2, has triclinic (P-1) symmetry. The structure displays N-H...S hydrogen bonding.