Synthesis of substituted N-(2'-nitrophenyl)pyrrolidine-2-carboxamides towards the design of proline-rich antimicrobial peptide mimics to eliminate bacterial resistance to antibiotics.

The treatment of diseases is under threat due to the increasing resistance of disease-causing bacteria to antibiotics. Likewise, free radical-induced oxidative stress has been implicated in several human disease conditions, such as cancer, stroke and diabetes. In the search for amino acid analogues with antibacterial and antioxidant properties as possible mimics of antimicrobial peptides, substituted N-(2'-nitrophenyl)pyrrolidine-2-carboxamides 4a-4k and N-(2'-nitrophenyl)piperidine-2-carboxamides 4l-4n have been synthesized via a two-step, one-pot amidation of the corresponding acids, using thionyl chloride with different amines in dichloromethane. The carboxamides were characterized by infrared and nuclear magnetic resonance spectroscopy, mass spectrometry and elemental analysis. Carboxamides 4a-4n were assayed against five Gram-positive and five Gram-negative bacterial strains using the broth micro-dilution procedure and compared to standard antibiotic drugs (streptomycin and nalidixic acid). 4b showed the highest antibacterial activity with a minimum inhibitory concentration (MIC) value of 15.6 µg/mL against Staphylococcus aureus. Pertinently, 4b and 4k are promising candidates for narrow-spectrum (Gram-positive) and broad-spectrum antibiotics, respectively. The antioxidant properties of the carboxamides were also evaluated using the 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical cation. 4a and 4k recorded the lowest IC50 values of 1.22 × 10-3 mg/mL (with DPPH) and 1.45 × 10-4 mg/mL (with ABTS), respectively. Notably, 4k recorded about 2.5 times better antioxidant capacity than the positive controls - ascorbic acid and butylated hydroxyanisole. These results bode well for N-aryl carboxamides as good mimics and substitutes for antimicrobial peptides towards mitigating bacterial resistance to antibiotics as well as ameliorating oxidative stress-related diseases.

Phytochemical study of Piliostigma thonningii, a medicinal plant grown in Nigeria.

Piliostigma thonningii (Schumach.) Milne-Redhead. (Leguminosae) is used for various medicinal purposes in African countries. Phytochemical investigation of P. thonningii yielded two compounds newly isolated from natural sources, 2ß-methoxyclovan-9α-ol (1), and methyl-ent-3ß-hydroxylabd-8(17)-en-15-oate (2), along with 14 known compounds (3-16). Compounds 1 and 4 (alepterolic acid) showed potential selectivity towards Trypanosoma brucei brucei with IC50 7.89 and 3.42 µM, respectively. Compound 2 showed activity towards T. brucei and Leishmania donovani Amastigote with IC50 3.84 and 7.82 µM, respectively. The structure activity relationship (SAR) of the isolated metabolites suggested that hydroxylation at C-2 enhances the antiprotozoal activity towards T. brucei in sesquiterpenes 1 and 3. Similarly hydroxylation at C-3 in labdane diterpenes elevates the antiprotozoal activity towards T. brucei.

Synthesis, crystal structure and in-silico evaluation of arylsulfonamide Schiff bases for potential activity against colon cancer.

This report presents a comprehensive investigation into the synthesis and characterization of Schiff base compounds derived from benzenesulfonamide. The synthesis process, involved the reaction between N-cycloamino-2-sulfanilamide and various substituted o-salicylaldehydes, resulted in a set of compounds that were subjected to rigorous characterization using advanced spectral techniques, including 1H NMR, 13C NMR and FT-IR spectroscopy, and single-crystal X-ray diffraction. Furthermore, an in-depth assessment of the synthesized compounds was conducted through Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) analysis, in conjunction with docking studies, to elucidate their pharmacokinetic profiles and potential. Impressively, the ADMET analysis showcased encouraging drug-likeness properties of the newly synthesized Schiff bases. These computational findings were substantiated by molecular properties derived from density functional theory (DFT) calculations using the B3LYP/6-31G* method within the Jaguar Module of Schrödinger 2023-2 from Maestro (Schrodinger LLC, New York, USA). The exploration of frontier molecular orbitals (HOMO and LUMO) enabled the computation of global reactivity descriptors (GRDs), encompassing charge separation (Egap) and global softness (S). Notably, within this analysis, one Schiff base, namely, 4-bromo-2-{N-[2-(pyrrolidine-1-sulfonyl)phenyl]carboximidoyl}phenol, 20, emerged with the smallest charge separation (ΔEgap = 3.5780 eV), signifying heightened potential for biological properties. Conversely, 4-bromo-2-{N-[2-(piperidine-1-sulfonyl)phenyl]carboximidoyl}phenol, 17, exhibited the largest charge separation (ΔEgap = 4.9242 eV), implying a relatively lower propensity for biological activity. Moreover, the synthesized Schiff bases displayed remarkeable inhibition of tankyrase poly(ADP-ribose) polymerase enzymes, integral in colon cancer, surpassing the efficacy of a standard drug used for the same purpose. Additionally, their bioavailability scores aligned closely with established medications such as trifluridine and 5-fluorouracil. The exploration of molecular electrostatic potential through colour mapping delved into the electronic behaviour and reactivity tendencies intrinsic to this diverse range of molecules.

Exploring the therapeutic potential of prolinamides as multi-targeted agents for Alzheimer's disease treatment: molecular docking and molecular dynamic simulation studies.

Alzheimer's disease (AD) presents a significant global health challenge, with its prevalence expected to rise sharply in the coming years. Despite extensive research, effective treatments addressing the multifaceted pathophysiology of AD remain elusive. This study investigates the therapeutic potential of twenty-seven prolinamides (P1 - P27), with the focus on their interactions with key proteins implicated in AD pathogenesis. Four of the compounds, namely; 10-((4-nitrophenyl)prolyl)-10 H-phenothiazine (P14), 2-((4-nitrophenyl)prolyl)isoindoline (P19), 1-(4-formylphenyl)-N-(p-tolyl)pyrrolidine-2-carboxamide (P22), and N,1-bis(4-nitrophenyl)pyrrolidine-2-carboxamide (P27) showed promising potential as Alzheimer's drug. In-silico approaches including molecular docking, molecular dynamic (MD) simulation, post md study, physicochemical and drug-likeness parameters were employed to ascertain the potential of these compounds as inhibitors of certain proteins implicated in the pathophysiology of Alzheimer's disease. Molecular docking and dynamics simulations demonstrated that P14, P19, P22 and P27 exhibited promising binding affinities towards crucial AD-associated proteins, including Beta-Secretase 1 (BACE1), Butyrylcholinesterase (BuChE), and Tau-tubulin kinase 2 (TTBK2). Structural stability analyses revealed that prolinamides, particularly P22 and P27 for BACE1 and P14 and P19 for BuChE, exhibited greater stability than their reference ligands, indicated by lower RMSD, RoG, and RMSF values. For BuChE, Rivastigmine had a docking score of -7.0 kcal/mol, a binding free energy (ΔGbind) of -22.19 ± 2.44 kcal/mol, RMSD of 1.361 ± 0.162 Å, RMSF of 9.357 ± 3.212 Å, and RoG of 22.919 ± 0.064 Å, whereas P19 exhibited a superior docking score of -10.3 kcal/mol, a significantly better ΔGbind of -33.74 ± 2.84 kcal/mol, RMSD of 1.347 ± 0.132 Å, RMSF of 8.164 ± 2.748 Å, and RoG of 22.868 ± 0.070 Å. Physicochemical and pharmacokinetic assessments affirmed the drug-likeness and bioavailability of P19 notably capable of penetrating the blood-brain barrier. Compounds P19 and P22, emerged as multi-targeted ligands, offering the potential for simultaneous modulation of multiple AD-related pathways. These findings highlight the possibilities of these compounds to be explored as novel therapeutic agents for AD. They also highlight the need for further experimental validation to confirm their efficacy and safety profiles, advancing them toward clinical application in AD management. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00250-z.

N-Cycloamino substituent effects on the packing architecture of ortho-sulfanilamide molecular crystals and their in silico carbonic anhydrase II and IX inhibitory activities.

In the search for new `sulfa drugs' with therapeutic properties, o-nitrosulfonamides and N-cycloamino-o-sulfanilamides were synthesized and characterized using techniques including 1H NMR, 13C NMR and FT-IR spectroscopy, and single-crystal X-ray diffraction (SC-XRD). The calculated density functional theory (DFT)-optimized geometry of the molecules showed similar conformations to those obtained by SC-XRD. Molecular docking of N-piperidinyl-o-sulfanilamide and N-indolinyl-o-sulfanilamide supports the notion that o-sulfanilamides are able to bind to human carbonic anhydrase II and IX inhibitors (hCA II and IX; PDB entries 4iwz and 5fl4). Hirshfeld surface analyses and DFT studies of three o-nitrosulfonamides {1-[(2-nitrophenyl)sulfonyl]pyrrolidine, C10H12N2O4S, 1, 1-[(2-nitrophenyl)sulfonyl]piperidine, C11H14N2O4S, 2, and 1-[(2-nitrophenyl)sulfonyl]-2,3-dihydro-1H-indole, C14H12N2O4S, 3} and three N-cycloamino-o-sulfanilamides [2-(pyrrolidine-1-sulfonyl)aniline, C10H14N2O2S, 4, 2-(piperidine-1-sulfonyl)aniline, C11H16N2O2S, 5, and 2-(2,3-dihydro-1H-indole-1-sulfonyl)aniline, C14H14N2O2S, 6] suggested that forces such as hydrogen bonding and π-π interactions hold molecules together and further showed that charge transfer could promote bioactivity and the ability to form biological interactions at the piperidinyl and phenyl moieties.

COVID-19 Pandemic: A Case for Phytomedicines.

Coronavirus disease 2019 (COVID-19) is an infection caused by a newly discovered coronavirus which was identified in Wuhan, China. The race is on globally to repurpose drugs for COVID-19 and develop a safe and effective vaccine against the disease. There is an urgent need to search for effective remedies against COVID-19 from the rich and extensive flora of Africa and the world. A literature search was conducted to obtain information on drugs with the potential for effectiveness in the treatment of COVID-19 based mostly on outcomes of preclinical studies and a few clinical investigations. This was considered important to this perspective as some of the identified mechanisms of action may be related to potential anti-COVID-19 actions of phytomedicines. The findings from the literature search were also used to establish the need for exploration of phytomedicines in the fight against COVID-19. This perspective identifies the need to preserve the rich tradition of herbal medicine in Africa, repositioning it by inculcating all aspects of discovery, development, and chemical evaluation of pharmaceuticals from medicinal plants for effective management of prevalent diseases. The identified mechanisms of action of current drugs under consideration for the treatment of COVID-19 include preventing fusion of SARS-CoV-2 with human cells; decrease acidity in endosomes, cell membrane-derived vesicles for transportation of the virus within the host cell and within which the virus can replicate; and blockade of the production of proinflammatory cytokines. Phytomedicines may possibly elicit either one or a combination of these effects. The case for the exploration of phytomedicines against COVID-19 is strengthened by the emergence of a number of conventional drugs from medicinal plants and the emergence of botanicals with proven efficacy for some medical conditions. Caution against indiscriminate use of medicinal plants in the guise of treating COVID-19 has been highlighted and the need for reliable preclinical and clinical studies.

Chemical and biological studies on Bridelia ferruginea grown in Nigeria.

Phytochemical investigation of the methanolic extract of dried leaves of Bridelia ferruginea led to the isolation and identification of fourteen compounds (1-14): compound 1 [mixture of palmitic, stearic and oleic acids], stearyl monoester of 2-O-ß-ᴅ-glucosylglycerol (2), 6ß-hydroxy-(20R)-24-ethylcholest-4-en-3-one (3a), 6ß-hydroxy-(20R)-24-ethylcholest-4,22-dien-3-one (3b), lutein (4), vomifoliol (5), corilagin (6), kaempferide-3-O-ß-ᴅ-glucoside (7), myricetin (8), isomericitrin (9), isoquercetin (10), myricitrin (11), quercitrin (12), rutin (13), and ß-sitosterol glucoside (14). The total extract exhibited moderate activity towards CB2 receptor and 90% inhibition against leishmanial pathogen Trypanosoma brucei. Compound 4 exhibited 73% displacement in CB2 receptor with IC50 56.47 µM, and 93% inhibition towards T. brucei with IC50 4.16 µM. Compound 11 showed 99% inhibition towards Escherichia coli with IC50 1.123 µM.

Antioxidant and Free Radical Scavenging Capacity of Seed and Shell Essential Oils Extracted from Abrus precatorius (L).

Essential oils from plants have been proven safe as natural antioxidants, and few are already marketed as digestive enhancers as well as in prevention of several degenerative diseases. This study evaluated the antioxidant capacity of seed and shell essential oils of Abrus precatorius (L), a herb used for ethno-medicinal practices in Nigeria. The essential oils were obtained by hydro-distillation. The ability of the oils to act as hydrogen/electrons donor or scavenger of radicals were determined by in-vitro antioxidant assays using 2,2-diphenyl-2-picryl-hydrazyl free radical (DPPH(.)) scavenging; 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical scavenging; lipid peroxide and nitric oxide radicals scavenging assays. The IC50 of the seed and shell oils (2.10 mg/mL and 1.20 mg/mL respectively) showed that antioxidant activity is higher than that for the standard drugs (3.20 mg/mL and 3.40 mg/mL) for the nitric oxide scavenging assay. The lipid peroxidation radical activity of the oils were similar to vitamin C, weak DPPH and ABTS radical scavenging activities were discovered in comparison to vitamin C and rutin. Generally, in the four antioxidant assays, a significant correlation existed between concentrations of the oils and percentage inhibition of free radicals and lipid peroxidation. The composition of A. precatorius essential oils reported earlier may account for their antioxidant capacity.

Composition and antioxidant activities of leaf and root volatile oils of Morinda lucida.

Morinda lucida (L.) Benth. (Rubiacae) is used in traditional medicine in many West African countries for the treatment of various human diseases. The leaves and roots of this plant were subjected to hydro-distillation to obtain volatile oils which were analyzed by high resolution GC/MS. Fifty compounds were identified in the leaf volatile oil and the major compounds were alpha-terpinene (17.8%) and beta-bisabolene (16.3%). In the root oil, 18 compounds were identified, the major constituents being 3-fluoro-p-anidine (51.8%) and hexadecanoic acid (12.0%). Antioxidant activities of the oils were examined using the DPPH, ABTS, reducing power and lipid peroxidation assays. All assays were concentration dependent with varying antioxidant potentials. The antioxidant activity of the root volatile oil of M. lucida was similar to that of the standard drugs used.