M. Shahjahan Kabir

A Very Active Cu-Catalytic System for the Synthesis of Aryl, Heteroaryl, and Vinyl Sulfides

cis-1,2-Cyclohexanediol (L3) has been shown to be an efficient and versatile bidentate O-donor ligand that provides a highly active Cu-catalytic system. It was more effective than diols such as trans-1,2-cyclohexanediol or ethylene glycol. This commercially available cis-1,2-cyclohexanediol ligand facilitated the Cu-catalyzed cross-coupling reactions of alkyl, aryl, or heterocyclic thiols with either alkyl, aryl, heterocyclic, or substituted vinyl halides. This new catalytic system promoted the mild and efficient stereo- and regiospecific synthesis of biologically important vinyl sulfides. The yields obtained using electron-rich substituted vinyl sulfides with this catalyst system are generally 75-98%. Most importantly, this singular catalyst system is extremely versatile and provides entry into a wide range of sulfides. This method is particularly noteworthy given its mild reaction conditions, simplicity, generality, and exceptional level of functional group tolerance.

First Application of an Efficient and Versatile Ligand for Copper-Catalyzed Cross-Coupling Reactions of Vinyl Halides with N-Heterocycles and Phenols

2-Pyridin-2-yl-1H-benzoimidazole L3 is presented as a new, efficient, and versatile bidentate N-donor ligand suitable for the copper-catalyzed formation of vinyl C-N and C-O bonds. This inexpensive and easily prepared ligand facilitates copper-catalyzed cross-coupling reactions of alkenyl bromides and iodides with N-heterocycles and phenols to afford the desired cross-coupled products in good to excellent yields with full retention of stereochemistry. This method is particularly noteworthy given its efficiency, that is, mild reaction conditions, low catalyst loading, simplicity, versatility, and exceptional level of functional group tolerance.

Stereo- and Regiospecific Cu-Catalyzed Cross-Coupling Reaction of Vinyl Iodides and Thiols: A Very Mild and General Route for the Synthesis of Vinyl Sulfides

A mild and efficient method for the copper-catalyzed formation of vinylic carbon-sulfur bonds has been developed. The desired vinyl sulfides are obtained in good to excellent yields, with full retention of stereochemistry. This method is particularly noteworthy given its mild reaction conditions, simplicity, and generality, as well as low cost of the catalyst system.

New classes of Gram-positive selective antibacterials: inhibitors of MRSA and surrogates of the causative agents of anthrax and tuberculosis.

Abstract An antimicrobial phenolic stilbene, (E)-3-hydroxy-5-methoxystilbene, 1 was recently isolated from the leaves of Comptonia peregrina (L.) Coulter and shown to possess inhibitory activity against several Gram-positive bacteria, including isolates of methicillin-resistant Staphylococcus aureus (MRSA), Mycobacterium bovis BCG, and avirulent Bacillus anthracis (Sterne strain), among others. These results prompted the design and synthesis of two new classes of compounds, phenoxystyrenes and phenothiostyrenes, as analogs of the natural antimicrobial stilbene. These and additional stilbenoid analogs were synthesized using new, efficient, copper-mediated coupling strategies. Minimum inhibitory concentration (MIC) antimicrobial assays were performed on all compounds prepared. These preliminary structure–activity relationship studies indicated that both new classes of synthetic analogs, as well as the stilbenes, show promising activity against Gram-positive bacteria when at least one phenolic moiety is present, but not when absent. The potencies of the phenolic phenoxystyrenes and phenothiostyrenes were found to be comparable to those of the phenolic stilbenes tested.

A new class of potential anti-tuberculosis agents: Synthesis and preliminary evaluation of novel acrylic acid ethyl ester derivatives

Novel acrylic acid ethyl ester derivatives were synthesized and evaluated as potential agents against Mycobacterium species. A versatile and efficient copper-catalyzed coupling process was developed and used to prepare a library of substituted acrylic acid ethyl ester analogs. Minimum inhibitory concentration assays indicated that two of these compounds 3 and 4 have greater in vitro activity against Mycobacterium smegmatis than rifampin, one of the current, first-line anti-mycobacterial chemotherapeutic agents. Moreover, members of this new class of compounds appear to exhibit a specific anti-mycobacterial effect and do not inhibit the growth of the other Gram-positive or Gram-negative species tested.

Study of the Cis to Trans Isomerization of 1-Phenyl-2,3-disubstituted Tetrahydro-β-carbolines at C(1). Evidence for the Carbocation-Mediated Mechanism

The present study was undertaken to shed light on the mechanism of the epimerization of cis-1,2,3-trisubstituted tetrahydro-beta-carbolines into the trans isomers via a potential carbocationic intermediate at C(1). In order to study the pathway involved in C(1)-N(2) bond cleavage, the electronic character of the carbon atom at C-1 was altered by substitution of electron-rich and electron-poor phenyl rings at this position. This provided direct evidence of the effects of charge at the proposed site of the carbocationic intermediate. In this regard, a diverse set of 1-(phenyl substituted)-2-benzyl-3-ethoxycarbonyl-1,2,3,4-tetrahydro-beta-carbolines has been synthesized via the Pictet-Spengler reaction by condensation of l-tryptophan derivatives with electron-poor and electron-rich aromatic aldehydes. The epimers involved in the isomerization mechanism were investigated by dynamic (1)H and (13)C NMR spectroscopic and X-ray crystallographic analyses. The kinetic studies, which involved conversion of cis diastereomers into their trans counterparts, were carried out in dilute TFA/CH(2)Cl(2). The 1-(4-methoxyphenyl) cis diastereomer epimerized at a much faster rate into the corresponding trans diastereomer than the related 1-(4-nitrophenyl) cis diastereomer epimerized. These observations provide support for the carbocationic intermediate in the C(1)-N(2) scission process. The understanding of this epimerization process is of importance when Pictet-Spengler reactions are carried out under acidic conditions during the synthesis of indole alkaloids.

Base-Mediated Stereospecific Synthesis of Aryloxy and Amino substituted Ethyl Acrylates

The stereospecific synthesis of aryloxy and amino substituted E- and Z-ethyl-3-acrylates is of interest because of their potential in the polymer industry and in medicinal chemistry. During work on a copper-catalyzed cross-coupling reaction of ethyl (E)- and (Z)-3-iodoacrylates with phenols and N-heterocycles, we discovered a very simple (nonmetallic) method for the stereospecific synthesis of aryloxy and amino substituted acrylates. To study this long-standing problem on the stereoselectivity of aryloxy and amino substituted acrylates, a series of O- and N-substituted nucleophiles was allowed to react with ethyl (E)- and (Z)-3-iodoacrylates. Screening of different bases indicated that DABCO (1,4-diazabicyclo[2.2.2]octane) afforded successful conversion of ethyl (E)- and (Z)-3-iodoacrylates into aryloxy and amino substituted ethyl acrylates in a stereospecific manner. Herein are the details of this DABCO-mediated stereospecific synthesis of aryloxy and amino substituted E- or Z-acrylates.

Design and synthesis of novel antimicrobials with activity against Gram-positive bacteria and mycobacterial species, including M. tuberculosis.

The alarming increase in bacterial resistance over the last decade along with a dramatic decrease in new treatments for infections has led to problems in the healthcare industry. Tuberculosis (TB) is caused mainly by Mycobacterium tuberculosis which is responsible for 1.4 million deaths per year. A world-wide threat with HIV co-infected with multi and extensively drug-resistant strains of TB has emerged. In this regard, herein, novel acrylic acid ethyl ester derivatives were synthesized in simple, efficient routes and evaluated as potential agents against several Mycobacterium species. These were synthesized via a stereospecific process for structure activity relationship (SAR) studies. Minimum inhibitory concentration (MIC) assays indicated that esters 12, 13, and 20 exhibited greater in vitro activity against Mycobacterium smegmatis than rifampin, one of the current, first-line anti-mycobacterial chemotherapeutic agents. Based on these studies the acrylic ester 20 has been developed as a potential lead compound which was found to have an MIC value of 0.4 μg/mL against Mycobacterium tuberculosis. The SAR and biological activity of this series is presented; a Michael-acceptor mechanism appears to be important for potent activity of this series of analogs.

Synthesis and minimum inhibitory concentrations of SK-03-92 against Staphylococcus aureus and other gram-positive bacteria

Staphylococcus aureus causes hundreds of thousands of infections and thousands of deaths per year in the United States. The emergence of methicillin-resistant S. aureus (MRSA), including community-associated methicillin-resistant S. aureus (CA-MRSA), has added to the problem. As MRSA continue to evolve, they are becoming resistant to more classes of antibiotics. In the past 20 years, only three new antibiotics have been approved for human use (linezolid, daptomycin, and tigecycline), and resistance to these three drugs has already emerged. New antibiotics are needed, and we have developed a promising drug candidate that may be applicable to treating MRSA, among other gram-positive bacterial infections. We have identified a novel synthetic drug, coded SK-03-92, that shows broad in vitro efficacy against a variety of gram-positive bacterial strains that include a number of strains of S. aureus. Besides the activity against gram-positive bacteria, this new drug also exhibits activity against Mycobacterium strains.

Pharmacokinetic/Toxicity Properties of the New Anti-Staphylococcal Lead Compound SK-03-92

Because of the potential of a new anti-staphylococcal lead compound SK-03-92 as a topical antibiotic, a patch, or an orally active drug, we sought to determine its safety profile and oral bioavailability. SK-03-92 had a high IC50 (125 μg/mL) in vitro against several mammalian cell lines, and mice injected intraperiteonally at the highest dose did not exhibit gross toxicity (e.g., altered gait, ungroomed, significant weight loss). Single dose (100 μg/g) pharmacokinetic (PK) analysis with formulated SK-03-92 showed that peak plasma concentration (1.64 μg/mL) was achieved at 20–30 min. Oral relative bioavailability was 8%, and the drug half-life was 20–30 min, demonstrating that SK-03-92 is likely not a candidate for oral delivery. Five-day and two-week PK analyses demonstrated that SK-03-92 plasma levels were low. Multi-dose analysis showed no gross adverse effects to the mice and a SK-03-92 peak plasma concentration of 2.12 μg/mL with the presence of significant concentrations of breakdown products 15 min after dosing. SK-03-92 appeared to be very safe based on tissue culture and mouse gross toxicity determinations, but the peak plasma concentration suggests that a pro-drug of SK-03-92 or preparation of analogs of SK-03-92 with greater bioavailability and longer half-lives are warranted.