Rajeshwar Singh

Discovery of a Novel Class of Boron-Based Antibacterials with Activity against Gram-Negative Bacteria

ABSTRACT Gram-negative bacteria cause approximately 70% of the infections in intensive care units. A growing number of bacterial isolates responsible for these infections are resistant to currently available antibiotics and to many in development. Most agents under development are modifications of existing drug classes, which only partially overcome existing resistance mechanisms. Therefore, new classes of Gram-negative antibacterials with truly novel modes of action are needed to circumvent these existing resistance mechanisms. We have previously identified a new a way to inhibit an aminoacyl-tRNA synthetase, leucyl-tRNA synthetase (LeuRS), in fungi via the oxaborole tRNA trapping (OBORT) mechanism. Herein, we show how we have modified the OBORT mechanism using a structure-guided approach to develop a new boron-based antibiotic class, the aminomethylbenzoxaboroles, which inhibit bacterial leucyl-tRNA synthetase and have activity against Gram-negative bacteria by largely evading the main efflux mechanisms in Escherichia coli and Pseudomonas aeruginosa. The lead analogue, AN3365, is active against Gram-negative bacteria, including Enterobacteriaceae bearing NDM-1 and KPC carbapenemases, as well as P. aeruginosa. This novel boron-based antibacterial, AN3365, has good mouse pharmacokinetics and was efficacious against E. coli and P. aeruginosa in murine thigh infection models, which suggest that this novel class of antibacterials has the potential to address this unmet medical need.

3-Acylamino-azetidin-2-one as a novel class of cysteine proteases inhibitors

A new class of inhibitors for cysteine proteases cathepsin B, L, K and S is described. These inhibitors are based on the beta-lactam ring designed to interact with the nucleophilic thiol of the cysteine in the active site of cysteine proteases. Some 3-acylamino-azetidin-2-one derivatives showed very potent inhibition activities for cathepsins L, K and S at the nanomolar or subnanomolar IC(50) values.

Boron-based phosphodiesterase inhibitors show novel binding of boron to PDE4 bimetal center.

We have used boron‐based molecules to create novel, competitive, reversible inhibitors of phosphodiesterase 4 (PDE4). The co‐crystal structure reveals a binding configuration which is unique compared to classical catechol PDE4 inhibitors, with boron binding to the activated water in the bimetal center. These phenoxybenzoxaboroles can be optimized to generate submicromolar potency enzyme inhibitors, which inhibit TNF‐α, IL‐2, IFN‐γ, IL‐5 and IL‐10 activities in vitro and show safety and efficacy for topical treatment of human psoriasis. They provide a valuable new route for creating novel potent anti‐PDE4 inhibitors.

Structure-activity relationships of 6-(aminomethylphenoxy)-benzoxaborole derivatives as anti-inflammatory agent.

A series of novel 6-(aminomethylphenoxy)benzoxaborole analogs was synthesized for the investigation of the structure-activity relationship of the inhibition of TNF-alpha, IL-1beta, and IL-6, from lipopolysaccharide stimulated peripheral blood mononuclear cells. Compounds 9d and 9e showed potent activity against all three cytokines with IC50 values between 33 and 83nM. Chloro substituted analog 9e (AN3485) is considered to be a promising lead for novel anti-inflammatory agent with a favorable pharmacokinetic profile.

Synthesis and antibacterial activity of the C-7 side chain of 3-aminoquinazolinediones

A novel series of bacterial topoisomerase (3-aminoquinazolinediones) inhibitors are described. The side-chain SAR against Gram-positive and Gram-negative organisms as well as DNA gyrase activity is reported.

Synthesis of substituted quinazolines

A novel and flexible synthetic route is described for the synthesis of 5,6,8-alkyl-7-methoxy-2-aminoquinazolines using dihydrobenzenes as key intermediates.

6-Acylamino-penam derivatives: synthesis and inhibition of cathepsins B, L, K, and S.

The synthesis of a new series of 6-acylamino penam derivatives and their inhibition of cysteine proteases cathepsins B, L, K, and S is described. The 6-acylamino-penam sulfone compounds showed excellent cathepsin L, K, and S inhibition activity with IC(50) values in the nanomolar and subnanomolar range.

Synthesis and antibacterial activity of 7-hydrazinoquinolones

A series of new C-7 substituted hydrazino quinolones and naphthyridines were prepared and tested for antibacterial activity. The hydrazine bridge at the C-7 position did not favor the antibacterial activity, whereas the nature of other substituents at N-1, C-5 and C-8 did noticeably influence the antibacterial activity. The 7-(1-aminomorpholino) derivatives exhibited superior antibacterial activity against Gram-positive and inferior activity against Gram-negative bacteria than the 7-(1-aminopiperazinyl) derivatives. Substitution of the quinolone at position-1 with cyclopropyl was the most beneficial for antibacterial activity among the series of compounds prepared.

Oxidation studies on .beta.-lactam antibiotics. The 6-(diacylamino)penicillins

S-Oxydation des composes du titre par lacide m-chloroperbenzoique; les sulfoxydes-1α obtenus sont rapidement transformes en sulfoxydes-1α desters de benzylpenicilline par traitement par Zn/NH 4 OAc; effet du solvant, de la temperature, de la fonction ester et du substituant en C-2

Synthesis of the novel antibacterial 6,8-dihydroxy-7-propyl-9H-pyrrolo[1,2-b][1,3]-benzoxazin-9-one

The total synthesis of 6,8-dihydroxy-7-propyl-9H-pyrrolo[1,2-b][1,3]benzoxazin-9-one, a novel antibacterial agent, is described. The key step in the synthesis is achieved via an oxidative cyclization of a phenol to the 2-position of a pyrrole using stoichiometric Pd(OAc)2. This provides a straightforward approach to the tricyclic structure of this prevously unreported template and future derivatives.