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      Mannich bases in medicinal chemistry and drug design

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          Abstract

          The biological activity of Mannich bases, a structurally heterogeneous class of chemical compounds that are generated from various substrates through the introduction of an aminomethyl function by means of the Mannich reaction, is surveyed, with emphasis on the relationship between structure and biological activity. The review covers extensively the literature reports that have disclosed Mannich bases as anticancer and cytotoxic agents, or compounds with potential antibacterial and antifungal activity in the last decade. The most relevant studies on the activity of Mannich bases as antimycobacterial agents, antimalarials, or antiviral candidates have been included as well. The review contains also a thorough coverage of anticonvulsant, anti-inflammatory, analgesic and antioxidant activities of Mannich bases. In addition, several minor biological activities of Mannich bases, such as their ability to regulate blood pressure or inhibit platelet aggregation, their antiparasitic and anti-ulcer effects, as well as their use as agents for the treatment of mental disorders have been presented. The review gives in the end a brief overview of the potential of Mannich bases as inhibitors of various enzymes or ligands for several receptors.

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          Highlights

          • Biological activities of structurally diverse Mannich bases are being reviewed.

          • Anticancer, antibacterial and antifungal activities are presented extensively.

          • Antimycobacterial, antimalarial and antiviral activities of Mannich bases are also covered.

          • Minor biological activities of Mannich bases are also summarized.

          • An overview of Mannich bases as inhibitors of enzymes and ligands for receptors is provided.

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          The incidence of invasive mycoses is increasing, especially among patients who are immunocompromised or hospitalized with serious underlying diseases. Such infections may be broken into two broad categories: opportunistic and endemic. The most important agents of the opportunistic mycoses are Candida spp., Cryptococcus neoformans, Pneumocystis jirovecii, and Aspergillus spp. (although the list of potential pathogens is ever expanding); while the most commonly encountered endemic mycoses are due to Histoplasma capsulatum, Coccidioides immitis/posadasii, and Blastomyces dermatitidis. This review discusses the epidemiologic profiles of these invasive mycoses in North America, as well as risk factors for infection, and the pathogens' antifungal susceptibility.
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            Display and analysis of patterns of differential activity of drugs against human tumor cell lines: development of mean graph and COMPARE algorithm.

            The objective of this study was to develop and investigate an approach to optimally detect, rank, display, and analyze patterns of differential growth inhibition among cultured cell lines. Such patterns of cellular responsiveness are produced by substances tested in vitro against disease-oriented panels of human tumor cell lines in a new anticancer screening model under development by the National Cancer Institute. In the first phase of the study, we developed a key methodological tool, the mean graph, which allowed the transformation of the numerical cell line response data into graphic patterns. These patterns were particularly expressive of differential cell growth inhibition and were conveniently amenable to further analyses by an algorithm we devised and implemented in the COMPARE computer program.
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              Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus.

              The emergence and spread of multidrug-resistant gram-positive bacteria represent a serious clinical problem. Telavancin is a novel lipoglycopeptide antibiotic that possesses rapid in vitro bactericidal activity against a broad spectrum of clinically relevant gram-positive pathogens. Here we demonstrate that telavancin's antibacterial activity derives from at least two mechanisms. As observed with vancomycin, telavancin inhibited late-stage peptidoglycan biosynthesis in a substrate-dependent fashion and bound the cell wall, as it did the lipid II surrogate tripeptide N,N'-diacetyl-L-lysinyl-D-alanyl-D-alanine, with high affinity. Telavancin also perturbed bacterial cell membrane potential and permeability. In methicillin-resistant Staphylococcus aureus, telavancin caused rapid, concentration-dependent depolarization of the plasma membrane, increases in permeability, and leakage of cellular ATP and K(+). The timing of these changes correlated with rapid , concentration-dependent loss of bacterial viability, suggesting that the early bactericidal activity of telavancin results from dissipation of cell membrane potential and an increase in membrane permeability. Binding and cell fractionation studies provided direct evidence for an interaction of telavancin with the bacterial cell membrane; stronger binding interactions were observed with the bacterial cell wall and cell membrane relative to vancomycin. We suggest that this multifunctional mechanism of action confers advantageous antibacterial properties.
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                Author and article information

                Contributors
                Journal
                Eur J Med Chem
                Eur J Med Chem
                European Journal of Medicinal Chemistry
                Elsevier Masson SAS.
                0223-5234
                1768-3254
                30 October 2014
                7 January 2015
                30 October 2014
                : 89
                : 743-816
                Affiliations
                [1]Petru Poni Institute of Macromolecular Chemistry, Department of Inorganic Polymers, 41A Aleea Gr. Ghica Vodă, Iaşi 700487, Romania
                Article
                S0223-5234(14)01004-6
                10.1016/j.ejmech.2014.10.076
                7115492
                25462280
                b3be5503-1483-44de-a84a-d75ae6e11f68
                Copyright © 2014 Elsevier Masson SAS. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 11 September 2014
                : 22 October 2014
                : 23 October 2014
                Categories
                Article

                Pharmacology & Pharmaceutical medicine
                aminomethylation,biological activity,drug design,mannich bases,structure–activity relationships

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