A pharmacophore model for inhibitors of
's DNA Gyrase B was developed, using computer-aided drug design. Subsequently, docking studies showed that 2,5(6)-substituted benzimidazole derivatives are ...promising molecules, as they possess key hydrogen bond donor/acceptor groups for an efficient interaction with this bacterial target. Furthermore, 5(6)-bromo-2-(2-nitrophenyl)-1
-benzimidazole, selected as a core molecule, was prepared on a multi-gram scale through condensation of 4-bromo-1,2-diaminobenzene with 2-nitrobenzaldehyde using a sustainable approach. The challenging functionalization of the 5(6)-position was carried out via palladium-catalyzed Suzuki-Miyaura and Buchwald-Hartwig amination cross-coupling reactions between
-protected-5-bromo-2-nitrophenyl-benzimidazole and aryl boronic acids or sulfonylanilines, with yields up to 81%. The final designed molecules (2-(aminophen-2-yl)-5(6)-substituted-1
-benzimidazoles), which encompass the appropriate functional groups in the 5(6)-position according to the pharmacophore model, were obtained in yields up to 91% after acid-mediated N-boc deprotection followed by Pd-catalyzed hydrogenation. These groups are predicted to favor interactions with DNA gyrase B residues Asn46, Asp73, and Asp173, aiming to promote an inhibitory effect.
Photodynamic therapy is witnessing a revival of its origins as a response to the rise of multi-drug resistant infections and the shortage of new classes of antibiotics. Photodynamic disinfection ...(PDDI) of microorganisms is making progresses in preclinical models and in clinical cases, and the perception of its role in the clinical armamentarium for the management of infectious diseases is changing. We review the positioning of PDDI from the perspective of its ability to respond to clinical needs. Emphasis is placed on the pipeline of photosensitizers that proved effective to inactivate biofilms, showed efficacy in animal models of infectious diseases or reached clinical trials. Novel opportunities resulting from the COVID-19 pandemic are briefly discussed. The molecular features of promising photosensitizers are emphasized and contrasted with those of photosensitizers used in the treatment of solid tumors. The development of photosensitizers has been accompanied by the fabrication of a variety of affordable and customizable light sources. We critically discuss the combination between photosensitizer and light source properties that may leverage PDDI and expand its applications to wider markets. The success of PDDI in the management of infectious diseases will ultimately depend on the efficacy of photosensitizers, affordability of the light sources, simplicity of the procedures, and availability of fast and efficient treatments.
Graphic abstract
The increasingly limited therapeutic options for the treatment of infections caused by multi-resistant Gram-negative bacteria due to the alarming increase in bacteria resistance, renewed interest in ...photodynamic inactivation (PDI) of bacteria. We address PDI of multi-resistant bacteria with a new family of cationic tetra-imidazolyl phthalocyanines bearing a diversity of cationizing alkylic chain sizes, degrees of cationization and coordinating metals. The antimicrobial activities of the phthalocyanines under white light against Gram-positive and Gram-negative bacteria have remarkable differences in efficacy. We relate their spectroscopic and photophysical properties with the generation of reactive oxygen species (ROS), biological performance and structural features. We show that sub-micromolar concentrations of a Zn(II) tetra-ethyl cationic phthalocyanine reduce colonies of Gram-negative bacteria (E. coli, P. aeruginosa) and C. albicans by 7 log units while leaving mammalian cells unharmed. This is a new lead to address hard-to-treat localized infections.
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•New cationic tetra-imidazolyl phthalocyanines were synthetized and characterized.•They exhibit photo-induced antibacterial activity against various microorganisms.•Our lead compound reduces colonies of bacteria and fungi by 7 log units.•The role of reactive oxygen species is elucidated for all studied systems.
Herein we describe the design of natural curcumin ester and ether derivatives and their application as potential bioplasticizers, to prepare photosensitive phthalate-free PVC-based materials. The ...preparation of PVC-based films incorporating several loadings of newly synthesized curcumin derivatives along with their standard solid-state characterization is also described. Remarkably, the plasticizing effect of the curcumin derivatives in the PVC material was found to be similar to that observed in previous PVC-phthalate materials. Finally, studies applying these new materials in the photoinactivation of
planktonic cultures revealed a strong structure/activity correlation, with the photosensitive materials reaching up to 6 log CFU reduction at low irradiation intensities.
Bacterial infections are a global health concern, particularly due to the increasing resistance of bacteria to antibiotics. Multi-drug resistance (MDR) is a considerable challenge, and novel ...approaches are needed to treat bacterial infections. Photodynamic inactivation (PDI) of microorganisms is increasingly recognized as an effective method to inactivate a broad spectrum of bacteria and overcome resistance mechanisms. This study presents the synthesis of a new cationic 5,15-di-imidazolyl porphyrin derivative and the impact of n-octanol/water partition coefficient (log
P
) values of this class of photosensitizers on PDI efficacy of
Escherichia coli
. The derivative with log
P
= –0.5,
IP-H-OH
2+
, achieved a remarkable 3 log CFU reduction of
E. coli
at 100 nM with only 1.36 J/cm
2
light dose at 415 nm, twice as effective as the second-best porphyrin
IP-H-Me
2+
, of log
P
= –1.35. We relate the rapid uptake of
IP-H-OH
2+
by
E. coli
to improved PDI and the very low uptake of a fluorinated derivative,
IP-H-CF
3
2+
, log
P
≈ 1, to its poor performance. Combination of PDI with cinnamaldehyde, a major component of the cinnamon plant known to alter bacteria cell membranes, offered synergic inactivation of
E. coli
(7 log CFU reduction), using 50 nM of
IP-H-OH
2+
and just 1.36 J/cm
2
light dose. The success of combining PDI with this natural compound broadens the scope of therapies for MDR infections that do not add drug resistance. In vivo studies on a mouse model of wound infection showed the potential of cationic 5,15-di-imidazolyl porphyrins to treat clinically relevant infected wounds.
Graphical Abstract
Nowadays, society’s widespread consumption of pharmaceutical drugs and the consequent accumulation of such compounds or their metabolites in effluents requires the development of efficient strategies ...and systems that lead to their effective degradation. This can be done through oxidative processes, in which tetrapyrrolic macrocycles (porphyrins, phthalocyanines) deserve special attention since they are among the most promising degradation catalysts. This paper presents a review of the literature over the past ten years on the major advances made in the development of oxidation processes of pharmaceuticals in aqueous solutions using tetrapyrrole-based catalysts. The review presents a brief discussion of the mechanisms involved in these oxidative processes and is organized by the degradation of families of pharmaceutical compounds, namely antibiotics, analgesics and neurological drugs, among others. For each family, a critical analysis and discussion of the fundamental roles of tetrapyrrolic macrocycles are presented, regarding both photochemical degradative processes and direct oxidative chemical degradation.
The combination of photodynamic therapy with antibiotics or antimicrobial peptides for inactivation of bacteria is an area of growing interest due to the synergistic effect already observed by many ...authors. It has been shown that the efficiency of this dual antimicrobial therapy is highly dependent on the structure of the photosensitizer, being tetrapyrrolic macrocycles the ones with most promising results. There are a few review articles in the recent literature describing the main microbiological results concerning this dual inactivation of bacteria, but none of them focus on the synthetic processes of these photosensitizers and their remarkable chemical versatility. Therefore, herein we present an overview on synthetic methodologies for preparation of tetrapyrrolic macrocycles and their conjugates with antibiotics or antimicrobial peptides, for use in dual inactivation of bacteria. This review will be divided in two sections concerning the physical or covalent combinations of PS with antibiotic/cationic peptides, followed by brief critical analysis on their corresponding antimicrobial outcomes.
Tetrapyrroclic macrocycles are one of the most promising photosensitizers in combination with antibiotics for dual inactivation of bacteria. This Review provides an overview regarding synthetic approaches for tetrapyrrolic macrocycles used as photosensitizers for dual inactivation of bacteria as well as a critical analysis on their antimicrobial effects.Pinto, Pereira, and co‐workers @UnivdeCoimbra @uegoficial with a Review article discussing the synthesis of photosensitizers based on tetrapyrrolic macrocycles for combination with antibiotics #PhotodynamicTherapy
The COVID-19 pandemic exposes our vulnerability to viruses that acquire the ability to infect our cells. Classical disinfection methods are limited by toxicity. Existing medicines performed poorly ...against SARS-CoV-2 because of their specificity to targets in different organisms. We address the challenge of mitigating known and prospective viral infections with a new photosensitizer for antimicrobial photodynamic therapy (aPDT). Photodynamic inactivation is based on local oxidative stress, which is particularly damaging to enveloped viruses. We synthesized a cationic imidazolyl chlorin that reduced by > 99.999% of the percentage inhibition of amplification of SARS-CoV-2 collected from patients at 0.2 µM concentration and 4 J cm
–2
. Similar results were obtained in the prevention of infection of human ACE2-expressing HEK293T cells by a pseudotyped lentiviral vector exhibiting the S protein of SARS-CoV-2 at its surface. No toxicity to human epidermal keratinocytes (HaCaT) cells was found under similar conditions. aPDT with this chlorin offers fast and safe broad-spectrum photodisinfection and can be repeated with low risk of resistance.
Graphical abstract
The amide peptide bond type linkage is one of the most natural conjugations available, present in many biological synthons and pharmaceutical drugs. Hence, aiming the direct conjugation of ...potentially biologically active compounds to phthalocyanines, herein we disclose a new strategy for direct modulation of phthalonitriles, inspired by an attractive synthetic strategy for the preparation of carboxamides based on palladium-catalyzed aminocarbonylation of aryl halides in the presence of carbon monoxide (CO) which, to our knowledge, has never been used to prepare amide-substituted phthalonitriles, the natural precursors for the synthesis of phthalocyanines. Some examples of phthalocyanines prepared thereof are also reported, along with their full spectroscopic characterization and photophysical properties initial assessment.
Over the last centuries, the influenza virus has been the cause of one of the deadliest and most concerning respiratory tract infections. Besides being annually responsible for thousands of deaths ...worldwide, it's capable of originating pandemics that can affect millions of people, like COVID-19. Photodynamic inactivation (PDI) is an emerging alternative solution for the treatment and control of viral infections and several studies have already shown that it can be efficient against influenza viruses. Herein we give a brief overview of key biological and epidemiological features of influenza and some insights on how to guide the development of new techniques for the management of influenza. This is followed by a review of in vitro and in vivo assays that have been carried out so far for the photodynamic inactivation of different influenza strains, using different families of photosensitizers (i.e. porphyrins, phthalocyanines, phenothiazinium dyes and analogues, among others) with diverse molecular size and charge (neutral, anionic or cationic). Finally, we give a brief perspective and update on the potential nasal inactivation of COVID-19 using PDI.
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