scholarly journals Semisynthetic Derivatives of Selected Amaryllidaceae Alkaloids as a New Class of Antimycobacterial Agents

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 6023
Author(s):  
Negar Maafi ◽  
Abdullah Al Mamun ◽  
Ondřej Janďourek ◽  
Jana Maříková ◽  
Kateřina Breiterová ◽  
...  
Keyword(s):  
Infectious Agent ◽  
Antimycobacterial Activity ◽  
Alamar Blue ◽  
Amaryllidaceae Alkaloids ◽  
New Class ◽  
Aromatic Esters ◽  
Antimycobacterial Agents ◽  
Hepatocellular Carcinoma Cell Line ◽  
Derivatives Of

The search for novel antimycobacterial drugs is a matter of urgency, since tuberculosis is still one of the top ten causes of death from a single infectious agent, killing more than 1.4 million people worldwide each year. Nine Amaryllidaceae alkaloids (AAs) of various structural types have been screened for their antimycobacterial activity. Unfortunately, all were considered inactive, and thus a pilot series of aromatic esters of galanthamine, 3-O-methylpancracine, vittatine and maritidine were synthesized to increase biological activity. The semisynthetic derivatives of AAs were screened for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Ra and two other mycobacterial strains (M. aurum, M. smegmatis) using a modified Microplate Alamar Blue Assay. The most active compounds were also studied for their in vitro hepatotoxicity on the hepatocellular carcinoma cell line HepG2. In general, the derivatization of the original AAs was associated with a significant increase in antimycobacterial activity. Several pilot derivatives were identified as compounds with micromolar MICs against M. tuberculosis H37Ra. Two derivatives of galanthamine, 1i and 1r, were selected for further structure optimalization to increase the selectivity index.

scholarly journals 5-Alkylamino-N-phenylpyrazine-2-carboxamides: Design, Preparation, and Antimycobacterial Evaluation

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1561
Author(s):  
Weronika Ambrożkiewicz ◽  
Marta Kučerová-Chlupáčová ◽  
Ondřej Janďourek ◽  
Klára Konečná ◽  
Pavla Paterová ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Clinical Importance ◽  
Infectious Agent ◽  
Antimycobacterial Activity ◽  
In Vitro Cytotoxicity ◽  
World Health ◽  
Health Organization ◽  
New Compounds ◽  
Derivatives Of

According to the World Health Organization, tuberculosis is still in the top ten causes of death from a single infectious agent, killing more than 1.7 million people worldwide each year. The rising resistance developed by Mycobacterium tuberculosis against currently used antituberculars is an imperative to develop new compounds with potential antimycobacterial activity. As a part of our continuous research on structural derivatives of the first-line antitubercular pyrazinamide, we have designed, prepared, and assessed the in vitro whole cell growth inhibition activity of forty-two novel 5-alkylamino-N-phenylpyrazine-2-carboxamides with various length of the alkylamino chain (propylamino to octylamino) and various simple substituents on the benzene ring. Final compounds were tested against Mycobacterium tuberculosis H37Ra and four other mycobacterial strains (M. aurum, M. smegmatis, M. kansasii, M. avium) in a modified Microplate Alamar Blue Assay. We identified several candidate molecules with micromolar MIC against M. tuberculosis H37Ra and low in vitro cytotoxicity in HepG2 cell line, for example, N-(4-hydroxyphenyl)-5-(pentylamino)pyrazine-2-carboxamide (3c, MIC = 3.91 µg/mL or 13.02 µM, SI > 38) and 5-(heptylamino)-N-(p-tolyl)pyrazine-2-carboxamide (4e, MIC = 0.78 µg/mL or 2.39 µM, SI > 20). In a complementary screening, we evaluated the in vitro activity against bacterial and fungal strains of clinical importance. We observed no antibacterial activity and sporadic antifungal activity against the Candida genus.

scholarly journals Dibasic Derivatives of Phenylcarbamic Acid Against Mycobacterial Strains: Old Drugs and New Tricks?

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2493 ◽  
Author(s):  
Ivan Malík ◽  
Jozef Csöllei ◽  
Ivan Solovič ◽  
Šárka Pospíšilová ◽  
Hana Michnová ◽  
...  
Keyword(s):  
Principal Component ◽  
Antimycobacterial Activity ◽  
Log P ◽  
In Vitro Susceptibility ◽  
Biological Assays ◽  
Sar Studies ◽  
Antimycobacterial Agents ◽  
Fitting Procedures ◽  
Derivatives Of

In order to provide a more detailed view on the structure–antimycobacterial activity relationship (SAR) of phenylcarbamic acid derivatives containing two centers of protonation, 1-[2-[({[2-/3-(alkoxy)phenyl]amino}carbonyl)oxy]-3-(dipropylammonio)propyl]pyrrolidinium oxalates (1a–d)/dichlorides (1e–h) as well as 1-[2-[({[2-/3-(alkoxy)phenyl]amino}carbonyl)oxy]-3-(di-propylammonio)propyl]azepanium oxalates (1i–l)/dichlorides (1m–p; alkoxy = butoxy to heptyloxy) were physicochemically characterized by estimation of their surface tension (γ; Traube’s stalagmometric method), electronic features (log ε; UV/Vis spectrophotometry) and lipophilic properties (log kw; isocratic RP-HPLC) as well. The experimental log kw dataset was studied together with computational logarithms of partition coefficients (log P) generated by various methods based mainly on atomic or combined atomic and fragmental principles. Similarities and differences between the experimental and in silico lipophilicity descriptors were analyzed by unscaled principal component analysis (PCA). The in vitro activity of compounds 1a–p was inspected against Mycobacterium tuberculosis CNCTC My 331/88 (identical with H37Rv and ATCC 2794, respectively), M. tuberculosis H37Ra ATCC 25177, M. kansasii CNCTC My 235/80 (identical with ATCC 12478), the M. kansasii 6509/96 clinical isolate, M. kansasii DSM 44162, M. avium CNCTC My 330/80 (identical with ATCC 25291), M. smegmatis ATCC 700084 and M. marinum CAMP 5644, respectively. In vitro susceptibility of the mycobacteria to reference drugs isoniazid, ethambutol, ofloxacin or ciprofloxacin was tested as well. A very unique aspect of the research was that many compounds from the set 1a–p were highly efficient almost against all tested mycobacteria. The most promising derivatives showed MIC values varied from 1.9 μM to 8 μM, which were lower compared to those of used standards, especially if concerning ability to fight M. tuberculosis H37Ra ATCC 25177, M. kansasii DSM 44162 or M. avium CNCTC My 330/80. Current in vitro biological assays and systematic SAR studies based on PCA approach as well as fitting procedures, which were supported by relevant statistical descriptors, proved that the compounds 1a–p represented a very promising molecular framework for development of ‘non-traditional’ but effective antimycobacterial agents.

A new group of potential antituberculotics: N-(2-pyridylmethyl)salicylamides and N-(3-pyridylmethyl)salicylamides

2011 ◽  
Vol 65 (1) ◽  
Author(s):  
Eva Petrlíková ◽  
Karel Waisser ◽  
Karel Palát ◽  
Jiří Kuneš ◽  
Jarmila Kaustová
Keyword(s):  
Hydrogen Bond ◽  
Mycobacterium Tuberculosis ◽  
Quantitative Relationship ◽  
Antimycobacterial Activity ◽  
Carbonyl Groups ◽  
In Vitro Activity ◽  
Salicylamide Derivatives ◽  
Layer Chromatography ◽  
Derivatives Of

AbstractAs a part of our systematic study of antimycobacterially active derivatives of salicylamides, a series of nineteen derivatives of N-(2-pyridylmethyl)salicylamides and N-(3-pyridylmethyl)salicylamides was synthesised. The compounds exhibited in vitro activity against Mycobacterium tuberculosis and M. avium. Their lipophilicity, R M, was measured by thin layer chromatography on silica gel impregnated with trioctadecylsilane and the logarithm of the partition coefficient (octanol-water), logP, was calculated. Both the parameters of lipophilicity correlated. The quantitative relationship between the structure and antimycobacterial activity was calculated. Antimycobacterial activity increased with an increase in lipophilicity. The N-(2-pyridylmethyl)salicylamide derivatives were more active than the derivatives of isomeric N-(3-pyridylmethyl)salicylamides. The geometry of compounds was calculated and the calculation was verified by measuring the length of the hydrogen bond between hydroxyl and carbonyl groups on the salicylic moiety.

Synthesis and Evaluation of Novel Fluorobenzimidazole Derivatives as Antibacterial and Antifungal Agents

2019 ◽  
Vol 4 (4) ◽  
pp. 209-215
Author(s):  
D. Joshi ◽  
R. Narigara ◽  
G. Jani ◽  
K. Parikh
Keyword(s):  
Bacterial Strains ◽  
Compound I ◽  
Substituted Anilines ◽  
Gram Negative ◽  
E Coli ◽  
New Class ◽  
Antibacterial And Antifungal ◽  
Derivatives Of ◽  
Multiple Step

A new class of fluorobenzimidazole derivatives (IIIa-j)was synthesized to investigate their antimicrobial potential. All the compounds were prepared by multiple step synthesis, initiating from the synthesis of 5-(difluoromethoxy)-1H-benzimidazole-2-thiol (I). The compound I was further reacted with different derivatives of 2-chloro-N-phenylacetamide (IIa-j) prepared by reacting differently substituted anilines with chloroacetylchloride and triethylamine in DMF (solvent); resulting in formation of fluorobenzimidazoles IIIa-j. The compounds IIIa-j were characterized by spectral analysis viz. 1H NMR, 13C NMR, mass spectra, elemental analysis and IR. All these compounds were screened in vitro for their antimicrobial activity against Gram-positive (S. aureus and E. faecalis) and Gram-negative bacterial (E. coli and P.aeruginosa) strains as well as fungi (A. niger and C. albicans). Some of the compounds exhibited promising results (in MIC) against Gram-negative bacterial strains.

Synthesis and in vitro Antiviral Properties of Amphiphilic Dinucleoside Phosphate Derivatives of 2′,3-dideoxycytidine (ddC)

1995 ◽  
Vol 6 (5) ◽  
pp. 320-326 ◽  
Author(s):  
H. Schott ◽  
M. P. Häussler ◽  
P. Gowland ◽  
A. Bender ◽  
H. von Briesen ◽  
...  
Keyword(s):  
Lipid Membranes ◽  
Micelle Formation ◽  
Human Monocytes ◽  
New Class ◽  
Antiviral Activities ◽  
Derivatives Of ◽  
Hiv 1

N4-hexadecyl-5′-0-(4-monomethoxytrityl)-2′-deoxycytidine-3′-hydrogenphosphonate and 5′-0-(4-monomethoxytrityl)-2′-deoxythymidine-3′-0-hydrogenphosphonate were condensed with 2′,3′-dideoxycytidine (ddC) according to the hydrogenphosphonate method to yield N4-hexadecyl-2′-deoxycytidylyl-(3′-5′)-2′,3′-dideoxycytidine (N4-hexadecyldC-ddC) and 2′-deoxythymidylyl-(3′-5′)-N4-palmitoyl-2′,3′-dideoxycytidine (dT-N4-palmddC). N4-palmitoyl-2′,3′-dideoxycytidine (N4-palmddC) was synthesized by reacting palmitic anhydride with ddC. Both dinucleoside phosphates have amphiphilic properties and represent a new class of ddC derivatives in which in the case of the dinucleosides, the ddC-5′-monophosphate is masked with lipophilic residues of variable stability. The ddC derivatives can be solubilized in water by micelle formation and, because they have lipophilic residues, they can be incorporated into the lipid membranes of liposomes. The ddC derivatives were shown to have antiviral activities comparable to those of AZT and ddC when tested in vitro against HIV-1-infected HeLa and H9 cells as well as infected human monocytes/macrophages.

Antimycobacterial 3-phenyl-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones and 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-dithiones substituted on phenyl and benzoxazine moiety in position 6

2011 ◽  
Vol 65 (3) ◽  
Author(s):  
Eva Petrlíková ◽  
Karel Waisser ◽  
Rafael Doležal ◽  
Pavel Holý ◽  
Jiří Gregor ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Antimycobacterial Activity ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Derivatives Of

AbstractA series of forty-five derivatives of 3-phenyl-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones and forty-five derivatives of 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-dithiones was synthesised. The compounds exhibited in-vitro activity against Mycobacterium tuberculosis, M. kansasii (two strains), and M. avium. The most active derivatives were more active than isonicotinhydrazide (INH). The quantitative relationships between the structure and antimycobacterial activity were calculated. The activity against M. tuberculosis increased with the lipophilicity of the substituents.

scholarly journals Versatility of 7-Substituted Coumarin Molecules as Antimycobacterial Agents, Neuronal Enzyme Inhibitors and Neuroprotective Agents

2017 ◽  
Author(s):  
Erika Kapp ◽  
Hanri Visser ◽  
Samantha L. Sampson ◽  
Sarel F. Malan ◽  
Elizabeth M. Streicher ◽  
...  
Keyword(s):  
Enzyme Inhibitors ◽  
Neuroblastoma Cells ◽  
Antimycobacterial Activity ◽  
Tuberculosis H37rv ◽  
Neuroprotective Agents ◽  
Human Neuroblastoma ◽  
Lead Compounds ◽  
Antimycobacterial Agents ◽  
Insight Into

An in vitro medium-throughput screen using M. tuberculosis H37Rv was employed to screen an in-house library of structurally diverse compounds for antimycobacterial activity.  From this initial screen, eleven 7-substituted coumarin derivatives with confirmed monoamine oxidase-B and cholinesterase inhibitory activities, demonstrated growth inhibition of more than 50% at a 50 µM concentration.  This prompted further exploration of all the 7-substituted coumarins in our library, nineteen in total, as potential antimycobacterial agents. Four derivatives showed promising antimycobacterial activity with MIC99 values of 8.31 – 29.70 µM and 44.15 – 57.17 µM on M. tuberculosis H37Rv in independent assays using Gaste-Fe and 7H9 + OADC media, respectively.   These compounds were found to bind to albumin which may explain the variations in MIC between the two assays.  Preliminary antimycobacterial evaluation of moxifloxacin resistant M. tuberculosis show that these compounds are able to maintain their activity in fluoroquinolone resistant mycobacteria.   Analysis of structure activity relationships for antimycobacterial versus neuronal enzyme inhibitory activity indicate that structural modification on position 4 and/or 7 of the coumarin scaffold may be utilized to improve selectivity towards either inhibition of neuronal enzymes or antimycobacterial effect.  Cytotoxicity evaluations of the compounds indicate moderate cytotoxicity with slight selectivity towards mycobacteria.  Further neuroprotective assays on SH-SY5Y human neuroblastoma cells indicate significant neuroprotection for selected compounds irrespective of their neuronal enzyme inhibitory properties.  These coumarin molecules are thus interesting lead compounds that may provide insight into the design of new antimicrobacterial and/or neuroprotective agents.

scholarly journals Chemoenzymatic Synthesis of New Aromatic Esters of Mono- and Oligosaccharides

Processes ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 1638
Author(s):  
Alina Ramona Buzatu ◽  
August E. Frissen ◽  
Lambertus A. M. van den Broek ◽  
Anamaria Todea ◽  
Marilena Motoc ◽  
...  
Keyword(s):  
Antimicrobial Properties ◽  
Degree Of Polymerization ◽  
Resonance Spectroscopy ◽  
Enzymatic Esterification ◽  
Alkyl Glycosides ◽  
New Class ◽  
Aromatic Esters ◽  
Novozyme 435 ◽  
Enzymatic Acylation ◽  
Derivatives Of

An efficient and convenient chemoenzymatic route for the synthesis of novel phenolic mono-, di- and oligosaccharide esters is described. Acetal derivatives of glucose, sucrose, lactose and inulin were obtained by chemical synthesis. The fully characterized pure sugar acetals were subjected to enzymatic esterification with 3-(4-hydroxyphenyl) propionic acid (HPPA) in the presence of Novozyme 435 lipase as a biocatalyst. The aromatic esters of alkyl glycosides and glucose acetal were obtained with good esterification yields, characterized by mass spectrometry (MALDI-TOF MS), infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy (1H NMR, 13C NMR). The synthesis of aromatic esters of disaccharide acetals was successful only for the enzymatic esterification of sucrose acetal. The new chemoenzymatic route allowed the synthesis of novel aromatic esters of inulin as the inulin monoacetal monoester and diester and the inulin diacetal monoester with a polymerization degree of two, as well as the inulin monoacetal monoester with a degree of polymerization of three, were obtained by enzymatic acylation of inulin acetals with HPPA. These compounds could represent a new class of sugar ester surfactants with enhanced bioactivity, antioxidative and antimicrobial properties and with potential application in drug delivery systems.

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