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1.
J Org Chem ; 88(24): 17088-17133, 2023 12 15.
Article in English | MEDLINE | ID: mdl-38051995

ABSTRACT

Solomonamides, a pair of macrocyclic peptide natural products originating from marine sources, have garnered significant attention within the synthetic community owing to their marked anti-inflammatory efficacy and intricate molecular architectures. In this paper, we present a very detailed investigation into solomonamides, including the challenges associated with the total synthesis, the evolution of our synthetic strategies, structural reassignment, synthesis of all possible stereoisomeric macrocycles, biological assessment, structure-activity relationship (SAR) studies, etc. Within the ambit of this total synthesis, diverse strategies for macrocyclization were rigorously explored, encompassing the Friedel-Crafts acylation, cyclization involving the aniline NH2 moiety, macrolactamization utilizing Gly-NH2, and Heck macrocyclization methodologies. In addition, an array of intriguing chemical transformations were devised, including but not limited to photo-Fries rearrangement, Wacker oxidation, ligand-free Heck macrocyclization, oxidative cleavage of indole, synthesis of contiguous stereocenters via substrate/reagent-controlled protocols, and simultaneous making and breaking of olefinic moieties. The findings of this investigation revealed a structurally simplified lead compound. Remarkably, the lead compound, while possessing structural simplification in comparison to the intricate solomonamide counterparts, demonstrates equipotent in vivo anti-inflammatory efficacy.


Subject(s)
Anti-Inflammatory Agents , Peptides , Structure-Activity Relationship , Cyclization , Oxidation-Reduction
2.
J Org Chem ; 88(9): 6209-6217, 2023 05 05.
Article in English | MEDLINE | ID: mdl-37071556

ABSTRACT

An improved method for the synthesis of a new quinolone class of antibiotics, which are exceptionally potent against gram-positive bacteria, has been developed and the structure confirmed by single-crystal X-ray analysis. In the course of synthesis, using either Chan-Lam coupling or Buchwald-Hartwig amination, we have shown that the careful choice of protecting group at the C4 position of the quinoline is required for selective amination at the C5 position and subsequent deprotection to avoid the formation of a novel pyrido[4,3,2-de]quinazoline tetracycle.


Subject(s)
Quinolones , Quinolones/chemistry , Structure-Activity Relationship , Anti-Bacterial Agents/chemistry , Gram-Positive Bacteria , 4-Quinolones
3.
J Med Chem ; 65(20): 13910-13934, 2022 10 27.
Article in English | MEDLINE | ID: mdl-36219779

ABSTRACT

Nosocomial infections caused by resistant Gram-positive organisms are on the rise, presumably due to a combination of factors including prolonged hospital exposure, increased use of invasive procedures, and pervasive antibiotic therapy. Although antibiotic stewardship and infection control measures are helpful, newer agents against multidrug-resistant (MDR) Gram-positive bacteria are urgently needed. Here, we describe our efforts that led to the identification of 5-amino-4-quinolone 111 with exceptionally potent Gram-positive activity with minimum inhibitory concentrations (MICs) ≤0.06 µg/mL against numerous clinical isolates. Preliminary mechanism of action and resistance studies demonstrate that the 5-amino-4-quinolones are bacteriostatic, do not select for resistance, and selectively disrupt bacterial membranes. While the precise molecular mechanism has not been elucidated, the lead compound is nontoxic displaying a therapeutic index greater than 500, is devoid of hemolytic activity, and has attractive physicochemical properties (clog P = 3.8, molecular weight (MW) = 441) that warrant further investigation of this promising antibacterial scaffold for the treatment of Gram-positive infections.


Subject(s)
Anti-Bacterial Agents , Quinolones , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Quinolones/pharmacology , Gram-Positive Bacteria , Microbial Sensitivity Tests , Drug Resistance, Multiple, Bacterial , Gram-Negative Bacteria
4.
J Org Chem ; 86(17): 11845-11861, 2021 09 03.
Article in English | MEDLINE | ID: mdl-34378926

ABSTRACT

We report synthesis of two diastereomeric structures previously proposed for the complex secondary metabolite pseurotin A2. Both structures were accessed from the same building blocks taking advantage of a stereodivergent nickel(II)-diamine-catalyzed 1,4-addition of a chiral 2-alkoxycarbonyl-3(2H)-furanone. Late-stage Csp-Csp3 cross-coupling of a highly functionalized bromoalkyne featured in the pseurotin A2 side-chain assembly. The work supports the 2016 stereochemical revision of pseurotin A2 and represents the first chemical synthesis of this natural product.


Subject(s)
Biological Products , Pyrrolidinones , Stereoisomerism
5.
Chem Asian J ; 14(24): 4572-4576, 2019 Dec 13.
Article in English | MEDLINE | ID: mdl-31512378

ABSTRACT

In an attempt towards understanding stereo-structure activity relationships (SSARs), we have prepared eight possible stereoisomers of solomonamide macrocycles, in particular, by changing the stereochemical pattern of non-peptide fragment AHMOA. Here, we have demonstrated different ways to construct three contiguous chiral centers present in solomonamide B macrocycle using substrate/reagent-controlled methods. These methods involve Brown crotylation, NHK reaction and Evans aldol addition as key steps to synthesize key non-peptide fragment. Further, these non-peptide fragments were converted to their corresponding macrocycles via ligand-free intramolecular Heck reaction.

6.
Org Biomol Chem ; 16(47): 9138-9142, 2018 12 05.
Article in English | MEDLINE | ID: mdl-30478463

ABSTRACT

Herein, we report the total synthesis of solomonamide A along with its structural revision for the first time. The natural product possesses very potent anti-inflammatory activity, and it contains a macrocyclic peptide having four consecutive stereocenters on an unnatural amino acid component. The key features in the present synthesis include the application of an Evans aldol reaction, ligand-free Heck macrocyclization and chemoselective oxidations. The challenging task of fixing the stereochemistry of OH at the C5-position was accomplished with the help of DFT calculations, applying a quantum-mechanical (QM)/NMR combined approach. Biological evaluation in a mouse paw edema model revealed that a low dose (0.3 mg kg-1) of the synthesized solomonamide A showed 74% reduction at 6 h, which was comparable to a high dose (10 mg kg-1) standard drug dexamethasone effect (75% at 6 h). Thus, we further confirmed the revised structure of solomonamide A.


Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Peptides, Cyclic/chemical synthesis , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Biological Products/chemical synthesis , Biological Products/chemistry , Biological Products/therapeutic use , Chemistry Techniques, Synthetic/methods , Cyclization , Edema/drug therapy , Mice , Oxidation-Reduction , Peptides, Cyclic/chemistry , Peptides, Cyclic/therapeutic use , Stereoisomerism
7.
ACS Omega ; 3(2): 2383-2389, 2018 Feb 28.
Article in English | MEDLINE | ID: mdl-30023831

ABSTRACT

To identify novel antitrypanosomal agents based on Janadolide, a potent macrocyclic polyketide-peptide hybrid, a macrolactonization strategy was explored. We prepared des-tert-butyl Janadolide and evaluated its antitrypanosomal activity. Our findings suggest that the tert-butyl group is necessary for the desired bioactivity.

8.
PLoS Negl Trop Dis ; 12(7): e0006648, 2018 07.
Article in English | MEDLINE | ID: mdl-30001342

ABSTRACT

Chandipura Virus (CHPV), a negative-stranded RNA virus belonging to the Rhabdoviridae family, has been previously reported to bring neuronal apoptosis by activating several factors leading to neurodegeneration. Following virus infection of the central nervous system, microglia, the ontogenetic and functional equivalents of macrophages in somatic tissues gets activated and starts secreting chemokines, thereby recruiting peripheral leukocytes into the brain parenchyma. In the present study, we have systemically examined the effect of CHPV on microglia and the activation of cellular signalling pathways leading to chemokine expression upon CHPV infection. Protein and mRNA expression profiles of chemokine genes revealed that CHPV infection strongly induces the expression of CXC chemokine ligand 10 (CXCL10) and CC chemokine ligand 5 (CCL5) in microglia. CHPV infection triggered the activation of signalling pathways mediated by mitogen-activated protein kinases, including p38, JNK 1 and 2, and nuclear factor κB (NF-kappaB). CHPV-induced expression of CXCL10 and CCL5 was achieved by the activation of p38 and NF-kappaB pathways. Considering the important role of inflammation in neurodegeneration, we have targeted NF-kappaB using a newly synthesised natural product nitrosporeusine analogue and showed incapability of microglial supernatant of inducing apoptosis in neurons after treatment.


Subject(s)
Alkaloids/administration & dosage , Antiviral Agents/administration & dosage , Central Nervous System Diseases/drug therapy , Microglia/immunology , NF-kappa B/immunology , Rhabdoviridae Infections/immunology , Vesiculovirus/physiology , Animals , Cell Line , Central Nervous System/immunology , Central Nervous System/virology , Central Nervous System Diseases/genetics , Central Nervous System Diseases/immunology , Central Nervous System Diseases/virology , Chemokine CCL5/genetics , Chemokine CCL5/immunology , Chemokine CXCL10/genetics , Chemokine CXCL10/immunology , Humans , Mice , Microglia/drug effects , Microglia/virology , NF-kappa B/genetics , Rhabdoviridae Infections/drug therapy , Rhabdoviridae Infections/genetics , Rhabdoviridae Infections/virology , Signal Transduction/drug effects , Vesiculovirus/drug effects , Vesiculovirus/genetics
9.
Int J Antimicrob Agents ; 50(3): 389-392, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28694231

ABSTRACT

Drug repurposing of non-antimicrobials is a novel method to augment a seriously depleted drug pipeline for targeting drug-resistant pathogens. This article highlights the potent antimicrobial activity of Ivacaftor against Staphylococcus aureus, including vancomycin- and other multidrug-resistant strains. The potent activity of Ivacaftor in vivo is also demonstrated in a murine neutropenic thigh infection model. Taken together, these results support the potential of Ivacaftor as an antimicrobial agent for the treatment of staphylococcal infections.


Subject(s)
Aminophenols/administration & dosage , Anti-Bacterial Agents/administration & dosage , Chloride Channel Agonists/administration & dosage , Drug Repositioning , Quinolones/administration & dosage , Staphylococcal Infections/drug therapy , Staphylococcus aureus/drug effects , Aminophenols/pharmacology , Animals , Anti-Bacterial Agents/pharmacology , Chloride Channel Agonists/pharmacology , Disease Models, Animal , Mice, Inbred BALB C , Quinolones/pharmacology , Treatment Outcome
10.
Eur J Med Chem ; 135: 89-109, 2017 Jul 28.
Article in English | MEDLINE | ID: mdl-28433779

ABSTRACT

Nitrosporeusines A and B are two recently isolated marine natural products with novel skeleton and exceptional biological profile. Interesting antiviral activity of nitrosporeusines and promising potential in curing various diseases, evident from positive data from various animal models, led us to investigate their anti-inflammatory potential. Accordingly, we planned and synthesized nitrosporeusines A and B in racemic as well as enantiopure forms. The natural product synthesis was followed by preparation of several analogues, and all the synthesized compounds were evaluated for in vitro and in vivo anti-inflammatory potential. Among them, compounds 25, 29 and 40 significantly reduced levels of nitric oxide (NO), reactive oxygen species (ROS) and pro-inflammatory cytokines. In addition, these compounds suppressed several pro-inflammatory mediators including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), nuclear factor-κB (NF-κB), and thereby can be emerged as potent anti-inflammatory compounds. Furthermore, all possible isomers of lead compound 25 were synthesized, characterized and profiled in same set of assays and found that one of the enantiomer (-)-25a was superior among them.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Biological Products/pharmacology , Cytokines/antagonists & inhibitors , Nitric Oxide/antagonists & inhibitors , Reactive Oxygen Species/antagonists & inhibitors , Alkaloids/chemistry , Alkaloids/isolation & purification , Alkaloids/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/isolation & purification , Biological Products/chemistry , Biological Products/isolation & purification , Cell Survival/drug effects , Cytokines/metabolism , Dose-Response Relationship, Drug , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Mice , Molecular Structure , Nitric Oxide/metabolism , RAW 264.7 Cells , Reactive Oxygen Species/metabolism , Structure-Activity Relationship
11.
Org Lett ; 18(13): 3178-81, 2016 07 01.
Article in English | MEDLINE | ID: mdl-27332700

ABSTRACT

The first total synthesis of the proposed structure of solomonamide B has been achieved. However, the (1)H and (13)C NMR spectral data of the synthesized compound was not exactly matching with that of the natural solomonamide B. This prompted us to revise the originally proposed structure, in particular, the stereochemistry of the nonpeptide part, which was confirmed by its total synthesis. During the course of the synthesis, we have developed an interesting hydroxy group directed Wacker oxidation of internal olefins in a macrocyclic setting.


Subject(s)
Peptides, Cyclic/chemical synthesis , Biological Products/chemical synthesis , Molecular Structure , Oxidation-Reduction , Stereoisomerism
12.
ACS Med Chem Lett ; 6(11): 1111-6, 2015 Nov 12.
Article in English | MEDLINE | ID: mdl-26617963

ABSTRACT

Known morpholine class antifungals (fenpropimorph, fenpropidin, and amorolfine) were synthetically modified through silicon incorporation to have 15 sila-analogues. Twelve sila-analogues exhibited potent antifungal activity against different human fungal pathogens such as Candida albicans, Candida glabrata, Candida tropicalis, Cryptococcus neoformans, and Aspergillus niger. Sila-analogue 24 (fenpropimorph analogue) was the best in our hands, which showed superior fungicidal potential than fenpropidin, fenpropimorph, and amorolfine. The mode of action of sila-analogues was similar to morpholines, i.e., inhibition of sterol reductase and sterol isomerase enzymes of ergosterol synthesis pathway.

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