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1.
Antibiotics (Basel) ; 10(3)2021 Mar 22.
Article in English | MEDLINE | ID: mdl-33810102

ABSTRACT

Marine natural products (MNPs) have been an important and rich source for antimicrobial drug discovery and an effective alternative to control drug resistant infections. Herein, we report bioassay guided fractionation of marine extracts from sponges Lendenfeldia, Ircinia and Dysidea that led us to identify novel compounds with antimicrobial properties. Tertiary amines or quaternary amine salts: aniline 1, benzylamine 2, tertiary amine 3 and 4, and quaternary amine salt 5, along with three known compounds (6-8) were isolated from a crude extract and MeOH eluent marine extracts. The antibiotic activities of the compounds, and their isolation as natural products have not been reported before. Using tandem mass spectrometry (MS) analysis, potential structures of the bioactive fractions were assigned, leading to the hit validation of potential compounds through synthesis, and commercially available compounds. This method is a novel strategy to overcome insufficient quantities of pure material (NPs) for drug discovery and development which is a big challenge for pharmaceutical companies. The antibacterial screening of the marine extracts has shown several of the compounds exhibited potent in-vitro antibacterial activity, especially against methicillin-resistant Staphylococcus aureus (MRSA) with minimum inhibitory concentration (MIC) values between 15.6 to 62.5 microg mL-1. Herein, we also report structure activity relationships of a diverse range of commercial structurally similar compounds. The structure-activity relationships (SAR) results demonstrate that modification of the amines through linear chain length, and inclusion of aromatic rings, modifies the observed antimicrobial activity. Several commercially available compounds, which are structurally related to the discovered molecules, showed broad-spectrum antimicrobial activity against different test pathogens with a MIC range of 50 to 0.01 µM. The results of cross-referencing antimicrobial activity and cytotoxicity establish that these compounds are promising potential molecules, with a favourable therapeutic index for antimicrobial drug development. Additionally, the SAR studies show that simplified analogues of the isolated compounds have increased bioactivity.

2.
Front Microbiol ; 11: 551189, 2020.
Article in English | MEDLINE | ID: mdl-33329419

ABSTRACT

Drug resistant bacteria have emerged, so robust methods are needed to evaluate combined activities of known antibiotics as well as new synthetic compounds as novel antimicrobial agents to treatment efficacy in severe bacterial infections. Marine natural products (MNPs) have become new strong leads in the drug discovery endeavor and an effective alternative to control infections. Herein, we report the bioassay guided fractionation of marine extracts from the sponges Lendenfeldia, Ircinia, and Dysidea that led us to identify novel compounds with antimicrobial properties. Chemical synthesis of predicted compounds and their analogs has confirmed that the proposed structures may encode novel chemical structures with promising antimicrobial activity against the medically important pathogens. Several of the synthetic analogs exhibited potent and broad spectrum in vitro antibacterial activity, especially against the Methicillin-resistant Staphylococcus aureus (MRSA) (MICs to 12.5 µM), Mycobacterium tuberculosis (MICs to 0.02 µM), uropathogenic Escherichia coli (MIC o 6.2 µM), and Pseudomonas aeruginosa (MIC to 3.1 µM). Checkerboard assay (CA) and time-kill studies (TKS) experiments analyzed with the a pharmacodynamic model, have potentials for in vitro evaluation of new and existing antimicrobials. In this study, CA and TKS were used to identify the potential benefits of an antibiotic combination (i.e., synthetic compounds, vancomycin, and rifampicin) for the treatment of MRSA and M. tuberculosis infections. CA experiments indicated that the association of compounds 1a and 2a with vancomycin and compound 3 with rifampicin combination have a synergistic effect against a MRSA and M. tuberculosis infections, respectively. Furthermore, the analysis of TKS uncovered bactericidal and time-dependent properties of the synthetic compounds that may be due to variations in hydrophobicity and mechanisms of action of the molecules tested. The results of cross-referencing antimicrobial activity, and toxicity, CA, and Time-Kill experiments establish that these synthetic compounds are promising potential leads, with a favorable therapeutic index for antimicrobial drug development.

3.
J Med Chem ; 61(8): 3595-3608, 2018 04 26.
Article in English | MEDLINE | ID: mdl-29558124

ABSTRACT

We recently reported the discovery of nontoxic cyclam-derived compounds that are active against drug-resistant Mycobacterium tuberculosis. In this paper we report exploration of the structure-activity relationship for this class of compounds, identifying several simpler compounds with comparable activity. The most promising compound identified, possessing significantly improved water solubility, displayed high levels of bacterial clearance in an in vivo zebrafish embryo model, suggesting this compound series has promise for in vivo treatment of tuberculosis.


Subject(s)
Antitubercular Agents/pharmacology , Aza Compounds/pharmacology , Heterocyclic Compounds, 1-Ring/pharmacology , Macrocyclic Compounds/pharmacology , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Bacterial Load/drug effects , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Drug Resistance, Bacterial , Heterocyclic Compounds, 1-Ring/chemical synthesis , Heterocyclic Compounds, 1-Ring/chemistry , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/chemistry , Metals, Heavy/chemistry , Microbial Sensitivity Tests , Molecular Structure , Mycobacterium marinum/drug effects , Solubility , Structure-Activity Relationship , Tuberculosis/drug therapy , Zebrafish
4.
J Med Chem ; 59(12): 5917-21, 2016 06 23.
Article in English | MEDLINE | ID: mdl-27214150

ABSTRACT

Tuberculosis (TB) accounted for 1.5 million deaths in 2014, and new classes of anti-TB drugs are required. We report a class of functionalized 1,8-disubstituted cyclam derivatives that display low micromolar activity against pathogenic mycobacteria. These compounds inhibit intracellular growth of Mycobacterium tuberculosis, are nontoxic to human cell lines, and are active against multidrug-resistant M. tuberculosis strains, indicating a distinct mode of action. These compounds warrant further appraisal as novel agents to control TB in humans.


Subject(s)
Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Organometallic Compounds/pharmacology , Tuberculosis, Multidrug-Resistant/drug therapy , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Cell Line , Dose-Response Relationship, Drug , Humans , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Conformation , Mycobacterium tuberculosis/growth & development , Organometallic Compounds/chemical synthesis , Organometallic Compounds/chemistry , Structure-Activity Relationship
5.
ACS Med Chem Lett ; 6(3): 329-33, 2015 Mar 12.
Article in English | MEDLINE | ID: mdl-25815155

ABSTRACT

A series of pyrido[3,4-d]azepines that are potent and selective 5-HT2C receptor agonists is disclosed. Compound 7 (PF-04781340) is identified as a suitable lead owing to good 5-HT2C potency, selectivity over 5-HT2B agonism, and in vitro ADME properties commensurate with an orally available and CNS penetrant profile. The synthesis of a novel bicyclic tetrasubstituted pyridine core template is outlined, including rationale to account for the unexpected formation of aminopyridine 13 resulting from an ammonia cascade cyclization.

6.
Org Lett ; 16(21): 5694-7, 2014 Nov 07.
Article in English | MEDLINE | ID: mdl-25343692

ABSTRACT

A chemoselective switch between reaction pathways by an alcohol cosolvent effect in a general SmI2-mediated synthesis of uracil derivatives is described. The method relies on the use of coordinating solvents to increase the redox potential of Sm(II) and results in a chemoselective 1,2-reduction (SmI2-H2O) or 1,2-migration via in situ generated N-acyliminium ions (SmI2-ethylene glycol, EG). This work exploits the mild conditions of the SmI2-mediated monoreduction of barbituric acids and offers an attractive protocol for the synthesis of uracil derivatives with biological activity from readily accessible building blocks.


Subject(s)
Alcohols/chemistry , Barbiturates/chemistry , Ethylene Glycol/chemistry , Iodides/chemistry , Ions/chemistry , Samarium/chemistry , Solvents/chemistry , Uracil/chemical synthesis , Molecular Structure , Oxidation-Reduction , Uracil/chemistry
7.
Org Lett ; 16(19): 5052-5, 2014 Oct 03.
Article in English | MEDLINE | ID: mdl-25247236

ABSTRACT

The first general method for the chemoselective synthesis of α,α-dideuterio alcohols directly from feedstock carboxylic acids under single electron transfer conditions using SmI2 is reported. This reaction proceeds after the activation of Sm(II) with a Lewis base, results in excellent levels of deuterium incorporation across a wide range of substrates, and represents an attractive alternative to processes mediated by pyrophoric alkali metal deuterides.


Subject(s)
Alcohols/chemical synthesis , Carboxylic Acids/chemistry , Deuterium/chemistry , Iodides/chemistry , Samarium/chemistry , Alcohols/chemistry , Combinatorial Chemistry Techniques , Metals, Alkali/chemistry , Molecular Structure , Stereoisomerism
8.
J Org Chem ; 79(24): 11988-2003, 2014 Dec 19.
Article in English | MEDLINE | ID: mdl-25232891

ABSTRACT

Samarium(II) iodide-water-amine reagents have emerged as some of the most powerful reagents (E° = -2.8 V) for the reduction of unactivated carboxylic acid derivatives to primary alcohols under single electron transfer conditions, a transformation that had been considered to lie outside the scope of the classic SmI2 reductant for more than 30 years. In this article, we present a detailed mechanistic investigation of the reduction of unactivated esters, carboxylic acids, and amides using SmI2-water-amine reagents, in which we compare the reactivity of three functional groups. The mechanism has been studied using the following: (i) kinetic, (ii) reactivity, (iii) radical clock, and (iv) isotopic labeling experiments. The kinetic data indicate that for the three functional groups all reaction components (SmI2, amine, water) are involved in the rate equation and that the rate of electron transfer is facilitated by base assisted deprotonation of water. Notably, the mechanistic details presented herein indicate that complexation between SmI2, water, and amines can result in a new class of structurally diverse, thermodynamically powerful reductants for efficient electron transfer to a variety of carboxylic acid derivatives. These observations will have important implications for the design and optimization of new processes involving Sm(II)-reduction of ketyl radicals.

9.
Chem Commun (Camb) ; 50(61): 8391-4, 2014 Aug 07.
Article in English | MEDLINE | ID: mdl-24942543

ABSTRACT

The mechanism of a recently reported first mono-reduction of cyclic 1,3-diesters (Meldrum's acids) to ß-hydroxy acids with SmI2-H2O has been studied using a combination of reactivity, deuteration, kinetic isotope and radical clock experiments. Most crucially, the data indicate that the reaction proceeds via reversible electron transfer and that water, as a ligand for SmI2, stabilizes the radical anion intermediate rather than only promoting the first electron transfer as originally proposed.


Subject(s)
Dioxanes/chemistry , Hydroxy Acids/chemistry , Samarium/chemistry , Deuterium/chemistry , Electron Transport , Iodides/chemistry , Kinetics , Oxidation-Reduction , Water/chemistry
10.
J Am Chem Soc ; 136(23): 8459-66, 2014 Jun 11.
Article in English | MEDLINE | ID: mdl-24810096

ABSTRACT

Mechanistic details pertaining to the SmI2-H2O-mediated reduction and reductive coupling of 6-membered lactones, the first class of simple unactivated carboxylic acid derivatives that had long been thought to lie outside the reducing range of SmI2, have been elucidated. Our results provide new experimental evidence that water enables the productive electron transfer from Sm(II) by stabilization of the radical anion intermediate rather than by solely promoting the first electron transfer as originally proposed. Notably, these studies suggest that all reactions involving the generation of ketyl-type radicals with SmI2 occur under a unified mechanism based on the thermodynamic control of the second electron transfer step, thus providing a blueprint for the development of a broad range of novel chemoselective transformations via open-shell electron pathways.

11.
Chemistry ; 20(15): 4222-6, 2014 Apr 07.
Article in English | MEDLINE | ID: mdl-24615806

ABSTRACT

The mechanism of the SmI2 -mediated reduction of unactivated esters has been studied using a combination of kinetic, radical clocks and reactivity experiments. The kinetic data indicate that all reaction components (SmI2 , amine, H2 O) are involved in the rate equation and that electron transfer is facilitated by Brønsted base assisted deprotonation of water in the transition state. The use of validated cyclopropyl-containing radical clocks demonstrates that the reaction occurs via fast, reversible first electron transfer, and that the electron transfer from simple Sm(II) complexes to aliphatic esters is rapid. Notably, the mechanistic details presented herein indicate that complexation between SmI2 , H2 O and amines affords a new class of structurally diverse, thermodynamically powerful reductants for efficient electron transfer to carboxylic acid derivatives as an attractive alternative to the classical hydride-mediated reductions and as a source of acyl-radical equivalents for CC bond forming processes.

12.
J Org Chem ; 79(6): 2522-37, 2014 Mar 21.
Article in English | MEDLINE | ID: mdl-24517639

ABSTRACT

Samarium(II) iodide-water complexes are ideally suited to mediate challenging electron transfer reactions, yet the effective redox potential of these powerful reductants has not been determined. Herein, we report an examination of the reactivity of SmI2(H2O)n with a series of unsaturated hydrocarbons and alkyl halides with reduction potentials ranging from -1.6 to -3.4 V vs SCE. We found that SmI2(H2O)n reacts with substrates that have reduction potentials more positive than -2.21 V vs SCE, which is much higher than the thermodynamic redox potential of SmI2(H2O)n determined by electrochemical methods (up to -1.3 V vs SCE). Determination of the effective redox potential demonstrates that coordination of water to SmI2 increases the effective reducing power of Sm(II) by more than 0.4 V. We demonstrate that complexes of SmI2(H2O)n arising from the addition of large amounts of H2O (500 equiv) are much less reactive toward reduction of aromatic hydrocarbons than complexes of SmI2(H2O)n prepared using 50 equiv of H2O. We also report that SmI2(H2O)n cleanly mediates Birch reductions of substrates bearing at least two aromatic rings in excellent yields, at room temperature, under very mild reaction conditions, and with selectivity that is not attainable by other single electron transfer reductants.


Subject(s)
Anthracenes/chemistry , Iodides/chemistry , Samarium/chemistry , Stilbenes/chemistry , Water/chemistry , Electron Transport , Hydrocarbons, Aromatic , Molecular Structure , Oxidation-Reduction
13.
Org Lett ; 16(4): 1092-5, 2014 Feb 21.
Article in English | MEDLINE | ID: mdl-24494855

ABSTRACT

The first general reduction of nitriles to primary amines under single electron transfer conditions is demonstrated using SmI2 (Kagan's reagent) activated with Lewis bases. The reaction features excellent functional group tolerance and represents an attractive alternative to the use of pyrophoric alkali metal hydrides. Notably, the electron transfer from Sm(II) to CN functional groups generates imidoyl-type radicals from bench stable nitrile precursors.


Subject(s)
Amines/chemical synthesis , Iodides/chemistry , Nitriles/chemistry , Samarium/chemistry , Amines/chemistry , Combinatorial Chemistry Techniques , Electron Transport , Lewis Bases/chemistry , Metals, Alkali/chemistry , Molecular Structure , Water
14.
J Am Chem Soc ; 136(6): 2268-71, 2014 Feb 12.
Article in English | MEDLINE | ID: mdl-24460078

ABSTRACT

Highly chemoselective direct reduction of primary, secondary, and tertiary amides to alcohols using SmI2/amine/H2O is reported. The reaction proceeds with C-N bond cleavage in the carbinolamine intermediate, shows excellent functional group tolerance, and delivers the alcohol products in very high yields. The expected C-O cleavage products are not formed under the reaction conditions. The observed reactivity is opposite to the electrophilicity of polar carbonyl groups resulting from the n(X) → π*(C═O) (X = O, N) conjugation. Mechanistic studies suggest that coordination of Sm to the carbonyl and then to Lewis basic nitrogen in the tetrahedral intermediate facilitate electron transfer and control the selectivity of the C-N/C-O cleavage. Notably, the method provides direct access to acyl-type radicals from unactivated amides under mild electron transfer conditions.


Subject(s)
Alcohols/chemistry , Amides/chemistry , Amines/chemistry , Samarium/chemistry , Water/chemistry , Molecular Structure , Oxidation-Reduction , Stereoisomerism
16.
J Am Chem Soc ; 135(42): 15702-5, 2013 Oct 23.
Article in English | MEDLINE | ID: mdl-24079360

ABSTRACT

Substrate-directable reactions play a pivotal role in organic synthesis, but are uncommon in reactions proceeding via radical mechanisms. Herein, we provide experimental evidence showing dramatic rate acceleration in the Sm(II)-mediated reduction of cyclic esters that is enabled by transient chelation between a directing group and the lanthanide center. This process allows unprecedented chemoselectivity in the reduction of cyclic esters using SmI2-H2O and for the first time proceeds with a broad substrate scope. Initial studies on the origin of selectivity and synthetic application to form carbon-carbon bonds are also disclosed.


Subject(s)
Alcohols/chemical synthesis , Electrons , Esters/chemistry , Iodides/chemistry , Samarium/chemistry , Water/chemistry , Alcohols/chemistry , Molecular Structure , Oxidation-Reduction
17.
Chem Soc Rev ; 42(23): 9155-83, 2013 Dec 07.
Article in English | MEDLINE | ID: mdl-24013846

ABSTRACT

Recently, samarium(II) iodide reductants have emerged as powerful single electron donors for the highly chemoselective reduction of common functional groups. Complete control of the product formation can be achieved on the basis of a judicious choice of a Sm(II) complex/proton donor couple, even in the presence of extremely sensitive functionalities (iodides, aldehydes). In most cases, the reductions are governed by thermodynamic control of the first electron transfer, which opens up new prospects for unprecedented transformations via radical intermediates under mild regio-, chemo- and diastereoselective conditions that are fully orthogonal to hydrogenation or metal-hydride mediated processes.

19.
J Am Chem Soc ; 134(30): 12751-7, 2012 Aug 01.
Article in English | MEDLINE | ID: mdl-22746316

ABSTRACT

Unsaturated lactones undergo reductive radical cyclizations upon treatment with SmI(2)-H(2)O to give decorated cycloheptanes in a single highly selective operation during which up to three contiguous stereocenters are generated. Furthermore, cascade processes involving lactones bearing two alkenes, an alkene and an alkyne, or an allene and an alkene allow "one-pot" access to biologically significant molecular scaffolds with the construction of up to four contiguous stereocenters. The cyclizations proceed by the trapping of radical anions formed by electron transfer reduction of the lactone carbonyl.


Subject(s)
Iodides/chemistry , Lactones/chemistry , Samarium/chemistry , Water/chemistry , Alkenes/chemistry , Alkynes/chemistry , Cyclization , Oxidation-Reduction , Stereoisomerism
20.
Nat Protoc ; 7(5): 970-7, 2012 Apr 26.
Article in English | MEDLINE | ID: mdl-22538848

ABSTRACT

The single-step synthesis of 3-hydroxy carboxylic acids from readily available Meldrum's acids involves a selective monoreduction using a SmI(2)-H(2)O complex to give products in high crude purity, and it represents a considerable advancement over other methods for the synthesis of 3-hydroxy acids. The protocol includes a detailed guide to the preparation of a single electron-reducing SmI(2)-H(2)O complex and describes two representative examples of the methodology: monoreduction of a fully saturated Meldrum's acid (5-(4-bromobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione) and tandem conjugate reduction-selective monoreduction of α,ß-unsaturated Meldrum's acid (5-(4-methoxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione). The protocol for selective monoreduction of Meldrum's acids takes ∼6 h to complete.


Subject(s)
Chemistry, Organic/methods , Dioxanes/chemistry , Hydroxy Acids/chemical synthesis , Iodides/chemistry , Samarium/chemistry , Water/chemistry
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