Kwasi Ohemeng

Amidino benzimidazole inhibitors of bacterial two-component systems

Amidino benzimidazoles have been identified as inhibitors of the bacterial KinA/Spo0F two-component system (TCS). Many of these inhibitors exhibit good in vitro antibacterial activity against a variety of susceptible and resistant Gram-positive organisms. The moiety at the 2-position of the benzimidazole was extensively modified. In addition, the regioisomeric benzoxazoles, heterocyclic replacements for the benzimidazole, have been synthesized and their activity against the TCS evaluated.

Novel inhibitors of bacterial two-component systems with gram positive antibacterial activity : Pharmacophore identification based on the screening hit closantel

This SAR study has shown that the salicylanilide is the pharmacophore for inhibition of the bacterial two-component system. Hydrophobic substituents improve the potency of inhibitors in this series; however, hydrophobicity is not the sole determinant for inhibition; structural and electronic requirements also exist. Closantel (1) was found to inhibit a two-component system and to have antibacterial activity against drug resistant S. aureus and E. faecium.

Synthesis and Inhibitory Activity of Novel Tri- and Tetracyclic Quinolines against Topoisomerases

A series of isoindolo[2,1-a]- and pyrrolo[1,2-a]quinolines were designed and synthesized for DNA-gyrase and topoisomerase-II inhibition studies. Some of the compounds showed significant activity against the enzymes.

Advances in DNA gyrase inhibitors.

The therapeutic use of DNA gyrase inhibitors, mainly quinolone antibacterials, has proven to be a tremendous success story in the treatment of bacterial infections. The rapid changes in quinolone research and development in recent years have produced several new quinolones: moxifloxacin, gatifloxacin, gemifloxacin and des-6-fluoroquinolone antibacterials. These newly developed compounds are equal or superior to existing ones in their potency, spectrum of activity, pharmacodynamics/pharmacokinetics and safety profiles. The recent discovery of non-fluoroquinolones and 2-pyridone antibacterials represents yet additional progress in the search for novel DNA gyrase inhibitors. Although these two classes of compounds are either in the discovery or early development phase, they extend the possibilities of establishing new structure-activity relationships and new chemotypes for DNA gyrase inhibition.

Synthesis and topoisomerase inhibitory activities of novel aza-analogues of flavones

Abstract Aseries of aza-flavones (3-hydroxy-2-phenyl-4-quinolones) were designed and synthesized as inhibitors of bacterial DNA-gyrase and mammalian topoisomerase II. Structure activity relationships of the compounds against each of the enzymes are discussed.

DNA gyrase inhibitory activity of ellagic acid derivatives

Ellagic acid was found to inhibit E. coli DNA gyrase supercoiling with approximately the same potency as nalidixic acid. Tricyclic analogs of ellagic acid, which vary in the number and position of the hydroxy groups as well as their replacement with halogens, have been synthesized. The biological activity of these analogs is discussed.

Patents on tetracycline and tetracycline derivatives as antimicrobials: January 1998 – October 2002

This review summarises patents claiming novel tetracyclines specified for antibacterial or antimicrobial use published from January 1998 to October 2002. A brief overview of the mode of action and important resistance mechanisms of the tetracycline class is presented. All of the novel tetracyclines cited were prepared through application of known chemistry to a small number of core tetracyclines with major focus upon the aromatic ring positions C-7, C-8 and C9; metal-catalysed aryl coupling reactions such as the Suzuki, Stille and Heck couplings were cited in numerous examples. Core tetracyclines used to derive novel chemical matter include tetracycline, doxycycline, sancycline and minocycline, among others, and the chemistry is claimed for alternative tetracycline templates. Novel tetracyclines were claimed for use against Gram-negative and Gram-positive bacteria including strains exhibiting tetracycline-specific efflux and ribosomal protection resistance. Tetracyclines were also claimed for use against cryptosporidium and as antifungal agents. In all cases, limited detailed information on biological profiles was cited.