New Compounds Hybrids 1H‐1,2,3‐Triazole‐Quinoline Against Plasmodium falciparum

Malaria is one of the most prevalent parasitic diseases in the world. The global importance of this disease, current vector control limitations, and the absence of an effective vaccine make the use of therapeutic antimalarial drugs the main strategy to control malaria. Chloroquine is a cost‐effective antimalarial drug with a relatively robust safety profile, or therapeutic index. However, chloroquine is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of chloroquine‐resistant strains, which have also been reported for Plasmodium vivax. However, the activity of 1,2,3‐triazole derivatives against chloroquine‐sensitive and chloroquine‐resistant strains of P. falciparum has been reported in the literature. To enhance the anti‐P. falciparum activity of quinoline derivatives, we synthesized 11 new quinoline‐1H‐1,2,3‐triazole hybrids with different substituents in the 4‐positions of the 1H‐1,2,3‐triazole ring, which were assayed against the W2‐chloroquine‐resistant P. falciparum clone. Six compounds exhibited activity against the P. falciparum W2 clone, chloroquine‐resistant, with IC₅₀ values ranging from 1.4 to 46 μm . None of these compounds was toxic to a normal monkey kidney cell line, thus exhibiting good selectivity indexes, as high 351 for one compound ( 11 ).     

Synthesis,Docking, In Vitro and In Vivo Antimalarial Activity of Hybrid 4‐aminoquinoline–1,3,5‐triazine Derivatives Against Wild and Mutant Malaria Parasites

A new series of hybrid 4‐aminoquinoline–1,3,5‐triazine derivatives was synthesized by a four‐step reaction. Target compounds were screened for in vitro antimalarial activity against chloroquine‐sensitive (3D‐7) and chloroquine‐resistant (RKL‐2) strains of Plasmodium falciparum. Compounds exhibited, by and large, good antimalarial activity against the resistant strain, while two of them, that is 8g and 8a, displayed higher activity against both the strains of P. falciparum. Additionally, docking study was performed on both wild (1J3I.pdb) and quadruple mutant (N51I, C59R, S108 N, I164L, 3QG2.pdb) type pf‐DHFR‐TS to highlight the structural features of hybrid molecules.     

Design,synthesis and in vitro antiplasmodial activity of some bisquinolines against chloroquine‐resistant strain

A series of novel bisquinoline compounds comprising N¹‐(7‐chloroquinolin‐4‐yl) ethane‐1,2‐diamine and 7‐chloro‐N‐(2‐(piperazin‐1‐yl)ethyl)quinolin‐4‐amine connected with 7‐chloro‐4‐aminoquinoline containing various amino acids is described. We have bio‐evaluated the compounds against both chloroquine‐sensitive (3D7) and chloroquine‐resistant (K1) strains of Plasmodium falciparum in vitro. Among the series, compounds 4 and 7 exhibited 1.8‐ and 10.6‐fold superior activity as compared to chloroquine (CQ; IC₅₀ = 0.255 ± 0.049 μm ) against the K1 strain with IC₅₀ values 0.137 ± 0.014 and 0.026 ± 0.007 μm , respectively. Furthermore, compound 7 also displayed promising activity against the 3D7 strain (IC₅₀ = 0.024 ± 0.003 μm ) of P. falciparum when compared to CQ. All the compounds in the series displayed resistance factor between 0.57 and 4.71 as against 51 for CQ. These results suggest that bisquinolines can be explored for further development as new antimalarial agents active against chloroquine‐resistant P. falciparum.     

Design and Synthesis of a New Class of 4‐Aminoquinolinyl‐ and 9‐Anilinoacridinyl Schiff Base Hydrazones as Potent Antimalarial Agents

A series of novel 4‐aminoquinolinyl and 9‐anilinoacridinyl Schiff base hydrazones have been synthesized and evaluated for their antimalarial activity. All compounds were evaluated in vitro for their antimalarial activity against chloroquine‐sensitive strain 3D7 and the chloroquine‐resistant K1 strain of Plasmodium falciparum and for cytotoxicity toward Vero cells. Compounds 17 , 20 , and 21 displayed good activity against the 3D7 strain with IC₅₀ values ranging from 19.69 to 25.38 nm . Moreover, compounds 16 , 17 , 21 , 24 , 32, and 33 exhibited excellent activities (21.64–54.26 nm ) against K1 strain and several compounds displayed β‐hematin inhibitory activity, suggesting that they act on the heme crystallization process such as CQ. Compounds were also found to be non‐toxic with good selectivity index.     

Piperazine‐linked 4‐aminoquinoline‐chalcone/ferrocenyl‐chalcone conjugates: Synthesis and antiplasmodial evaluation

A series of piperazine‐linked 4‐aminoquinoline‐chalcone/ferrocenyl‐chalcone conjugates were prepared with a view to evaluate their activities against Plasmodium falciparum. The synthesized conjugates had in vitro IC₅₀ values from 0.41 to 2.38 μm against chloroquine‐resistant and mefloquine‐sensitive W2 strain of P. falciparum. The submicromolar activities of most of the synthesized conjugates suggest that such molecular frameworks can act as therapeutic templates for the design and synthesis of new antimalarials.     

Design,synthesis, and antiprotozoal evaluation of new 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline derivatives

A series of new 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline derivatives was synthesized, and the compounds were screened in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiparasitic activity with IC₅₀ values in the μm range. The in vitro cytotoxicity of these molecules was assessed by incubation with human HepG2 cells; for some derivatives, cytotoxicity was observed at significantly higher concentrations than antiparasitic activity. The 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline 1h was identified as the most potent antimalarial candidate with ratios of cytotoxic‐to‐antiparasitic activities of 107 and 39 against a chloroquine‐sensitive and a chloroquine‐resistant strain of P. falciparum, respectively. As the telomeres of the parasite P. falciparum are the likely target of this compound, we investigated stabilization of the Plasmodium telomeric G‐quadruplexes by our phenanthroline derivatives through a FRET melting assay. The ligands 1f and 1m were noticed to be more specific for FPf8T with higher stabilization for FPf8T than for the human F21T sequence.     

Synthesis and Biological Evaluation of Tricyclic Guanidine Analogues of Batzelladine K for Antimalarial,Antileishmanial, Antibacterial,Antifungal, and Anti‐HIV Activities

Fifty analogues of batzelladine K were synthesized and evaluated for in vitro antimalarial (Plasmodium falciparum), antileishmanial (Leishmania donovani), antimicrobial (panel of bacteria and fungi), antiviral (HIV‐1) activities. Analogues 14h and 20l exhibited potential antimalarial activity against chloroquine‐sensitive D6 strain with IC₅₀ 1.25 and 0.88 μm and chloroquine‐resistant W2 strain with IC₅₀ 1.64 and 1.07 μm , respectively. Analogues 12c and 14c having nonyl substitution showed the most potent antileishmanial activity with IC₅₀ 2.39 and 2.78 μm and IC₉₀ 11.27 and 12.76 μm , respectively. Three analogues 12c , 14c, and 14i were the most active against various pathogenic bacteria and fungi with IC₅₀ < 3.02 μm and MIC/MBC/MFC <6 μm . Analogue 20l having pentyl and methyl substituents on tricycle showed promising activities against all pathogens. However, none was found active against HIV‐1. Our study demonstrated that the tricyclic guanidine compounds provide new structural class for broad spectrum activity.     

Synthesis of thiazolyl hydrazonothiazolamines and 1,3,4‐thiadiazinyl hydrazonothiazolamines as a class of antimalarial agents

Novel thiazolyl hydrazonothiazolamines and 1,3,4‐thiadiazinyl hydrazonothiazolamines were synthesized by a facile one‐pot multicomponent approach by the reaction of 2‐amino‐4‐methyl‐5‐acetylthiazole, thiosemicarbazide or thiocarbohydrazide and phenacyl bromides or 3‐(2‐bromoacetyl)‐2H‐chromen‐2‐ones in acetic acid with good to excellent yields. These new compounds were screened in vitro for their antimalarial activity; among them, four compounds, 4h, 4i, 4k, 4l , showed moderate activity with half‐maximal inhibitory concentration (IC₅₀) values of 3.2, 2.7, 2.7, and 2.8 and 3.2, 3.2, 3.1, and 3.5 μM against chloroquine‐sensitive and ‐resistant strains of Plasmodium falciparum, respectively. Compound 4l inhibited the ring stage growth of P. falciparum 3D7 at an IC₉₀ concentration of 12.5 µM in a stage‐specific assay method, where the culture is incubated with specific stages of P. falciparum for 12 hr, and no activity was found against the trophozoite and schizont stages, confirming that 4l may have potent action against the ring stage of P. falciparum.     

Novel 4-Aminoquinoline-Pyrimidine Based Hybrids with Improved in Vitro and in Vivo Antimalarial Activity

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7‐Chloroquinoline–isatin Conjugates: Antimalarial,Antitubercular, and Cytotoxic Evaluation

A series of twenty piperazine‐tethered 7‐chloroquinoline–isatin hybrids have been synthesized via either direct nucleophilic substitution or Cu(Ι)Cl‐mediated Mannich reaction. These new conjugates were evaluated for their antimalarial and antitubercular efficacy against a chloroquine‐resistant strain of Plasmodium falciparum and Mycobacterium tuberculosis, respectively, while the cytotoxic profiles were evaluated against 3T6 cell line, a permanent mouse embryonic fibroblast cell line. The most potent of the test compound with IC₅₀ of 0.22 μm against W2 strain of P. falciparum and 31.62 μm against the embryonic fibroblast cell line (cytotoxicity) displayed a high selective index of 143.73.     

Preparation and antiplasmodial activity of 3',4'‐dihydro‐1'H‐spiro(indoline‐3,2'‐quinolin)‐2‐ones

A series of 3',4'‐dihydro‐1'H‐spiro(indoline‐3,2'‐quinolin)‐2‐ones were prepared by the inverse‐electron‐demand aza‐Diels–Alder reaction (Povarov reaction) of imines derived from isatin and substituted anilines, and the electron‐rich alkenes trans‐isoeugenol and 3,4‐dihydro‐2H‐pyran. These compounds were assessed for in vitro antiplasmodial activity against drug‐sensitive and drug‐resistant forms of the P. falciparum parasite. Three compounds derived from 3,4‐dihydro‐2H‐pyran and four compounds derived from trans‐isoeugenol showed antiplasmodial activity in the low micromolar range against the drug‐resistant FCR‐3 strain (1.52–4.20 µM). Only compounds derived from trans‐isoeugenol showed antiplasmodial activity against the drug‐sensitive 3D7 strain (1.31–1.80 µM).     

Synthesis and antimalarial activity of ethylene glycol oligomeric ethers of artemisinin

Objectives The aim of this study was to synthesize a series of ethylene glycol ether derivatives of the antimalarial drug artemisinin, determine their values for selected physicochemical properties and evaluate their antimalarial activity in vitro against Plasmodium falciparum strains. Methods The ethers were synthesized in a one‐step process by coupling ethylene glycol moieties of various chain lengths to carbon C‐10 of artemisinin. The aqueous solubility and log D values were determined in phosphate buffered saline (pH 7.4). The derivatives were screened for antimalarial activity alongside artemether and chloroquine against chloroquine‐sensitive (D10) and moderately chloroquine‐resistant (Dd2) strains of P. falciparum. Key findings The aqueous solubility within each series increased as the ethylene glycol chain lengthened. The IC50 values revealed that all the derivatives were active against both D10 and Dd2 strains. All were less potent than artemether irrespective of the strain. However, they proved to be more potent than chloroquine against the resistant strain. Compound 8 , featuring three ethylene oxide units, was the most active of all the synthesized ethers. Conclusions The conjugation of dihydroartemisinin to ethylene glycol units of various chain lengths through etheral linkage led to water‐soluble derivatives. The strategy did not result in an increase of antimalarial activity compared with artemether. It is nevertheless a promising approach to further investigate and synthesize water‐soluble derivatives of artemisinin that may be more active than artemether by increasing the ethylene glycol chain length.     

6‐Hydrogen‐8‐Methylquinolones Active Against Replicating and Non‐replicating Mycobacterium tuberculosis

The screening of an in‐house quinolones library against Mycobacterium tuberculosis (Mtb) H₃₇Rv, followed by a first cycle of optimization, yielded 6‐hydrogen‐8‐methyl derivatives endowed with good potency. The antitubercular activity also encompassed the bacteria in a non‐replicating state (NRP‐TB) with minimum inhibitory concentration values lower than those of the reference agent, moxifloxacin. Among the best compounds, 11w and 11ai , characterized by a properly substituted piperidine at the C‐7 position, were active against single‐drug‐resistant (SDR‐TB) Mtb strains, maintaining overall good potency also against ciprofloxacin‐resistant Mtb. This study expands the body of SAR around antitubercular quinolones leading to reconsider the role played by the usual fluorine atom at the C‐6 position. Further elaboration of the 6‐hydrogen‐8‐methylquinolone scaffold, with a particular focus on the C‐7 position, is expected to give even more potent congeners holding promise for shortening the current anti‐TB regimen.     

Synthesis and In Vitro Antibacterial Activity of 7‐(3‐Alkoxyimino‐4‐methyl‐4‐methylaminopiperidin‐1‐yl)‐fluoroquinolone Derivatives

A series of novel 7‐(3‐alkoxyimino‐4‐methyl‐4‐methylaminopiperidin‐1‐yl)fluoroquinolone derivatives were designed, synthesized, and characterized by ¹H‐NMR, MS, and HRMS. These fluoroquinolones were evaluated for their in‐vitro antibacterial activity against representative Gram‐positive and Gram‐negative strains. Generally, all of the target compounds have considerable antibacterial activity against the tested forty strains, and exhibit exceptional potency in inhibiting the growth of methicillin‐sensitive Staphylococcus aureus (MSSA) and methicillin‐resistant S. aureus (MRSA) ATCC33591 (MICs: 0.06 to 2 μg/mL). In particular, compounds 14 , 19 , 28 , and 29 are fourfold more potent than ciprofloxacin against MSSA 08‐49. Compounds 23 , 26 , and 27 are twofold more potent than ciprofloxacin against MRSA ATCC33591 and MSSA ATCC29213. In addition, compound 14 exhibits excellent activity (MIC: 0.06 μg/mL) against Acinetobactes calcoaceticus, which is two‐ to 16‐fold more potent than the reference drugs gemifloxacin, levofloxacin, and ciprofloxacin.     

Tetramethylpiperidine‐substituted phenazines as novel anti‐plasmodial agents

Two novel derivatives of clofazimine [3‐(p‐chloroanilino)‐10‐(p‐chlorophenyl)‐2,10‐dihydro‐2‐isopropylimino)phenazine] and the tetramethylpiperidine (TMP)‐substituted phenazines, B4119 [3‐(3‐chloro‐4‐fluoroanilino)‐10‐(3‐chloro‐4‐fluorophenyl)‐2,10‐dihydro‐2(2,2,6,6‐tetramethylpiper‐4‐ylimino)phenazine] and B4158 [3‐(4‐isopropylanilino)‐10‐(4‐isopropylphenyl)‐2,10‐dihydro‐2‐(2,2,6,6‐tetramethylpiper‐4‐ylimino)phenazine] (1–8 μM), were evaluated for activity against chloroquin‐, quinine‐, and sulfadoxine/pyrimethamine‐sensitive and ‐resistant strains of Plasmodium falciparum in vitro, as well as for their effects on polymerisation of haeme to β‐hematin. By using microscopic and flow cytometric methods, it was found that B4119 and B4158, but not clofazimine, inhibited the growth of sensitive, as well as resistant strains of P. falciparum with IC₅₀ values between 0.22 and 0.7 μM, indicating lack of cross‐resistance. Augmentation of anti‐plasmodial activity was observed when B4119 and B4158 were used in combination with chloroquin or mefloquine. Inhibition of the growth of P. falciparum was associated with interference with haeme polymerisation to β‐hematin in vitro, while administration of B4119 to P. berghei‐infected mice was accompanied by a significant reduction in parasitemia and improved therapeutic activity was observed when this agent was combined with chloroquin. The data presented in this study demonstrate that the TMP‐substitution at position 2 on the phenazine nucleus of riminophenazines confers anti‐plasmodial activity on these compounds. These may prove to be useful forerunners in the design of novel anti‐plasmodial pharmacologic agents. Drug Dev. Res. 50:195–202, 2000. © 2000 Wiley‐Liss, Inc.     

Computational Studies on the Resistance of Penicillin‐Binding Protein 2B (PBP2B) of Wild‐type and Mutant Strains of Streptococcus pneumoniae Against β‐Lactam Antibiotics

Mutations within transpeptidase domain of penicillin‐binding protein 2B of the strains of Streptococcus pneumoniae leads to resistance against β‐lactam antibiotics. To uncover the important residues responsible for sensitivity and resistance, the recently determined three dimensional structures of penicillin‐binding protein 2B of both wild‐type R6 (sensitive) and mutant 5204 (resistant) strains along with the predicted structures of other mutant strains G54, Hungary19A‐6 and SP195 were considered for the interaction study with β‐lactam antibiotics using induced‐fit docking of Schrödinger. Associated binding energies of the complexes and their intermolecular interactions in the binding site clearly show that the wild‐type R6 as sensitive, mutant strains 5204 and G54 as highly resistant, and the mutant strains Hungary19A‐6 and SP195 as intermediate resistant. The study also reveals that the mutant strains Hungary19A‐6 and SP195 exhibit intermediate resistant because of the existence of mutations till the intermediate 538th and 516th positions, respectively, and not till the end of the C‐terminus. Furthermore, our investigations show that if the mutations are extended till the end of the C terminus, then the antibiotic resistance of induced‐mutated strains increases from intermediate to high as in the strains 5204 and G54. The binding patterns obtained in the study are useful in designing potential inhibitors against multidrug resistant S. pneumoniae.     

Synthesis and biological evaluation of some pyrazole derivatives as anti-malarial agents

Novel series of pyrazole derivatives were synthesized and tested for their in vivo anti‐malarial activity using mice infected with chloroquine sensitive P. berghei at a dose level of 50 µmol/kg. The most active compounds were further tested in vitro against chloroquine resistant (RKL9) strain of P. falciparum. The in vivo anti‐malarial activity study indicated that compounds 2a, 2b, 8a and 8b had mean percent suppression of 85%, 83%, 95% and 97%, respectively at equimolar dose level of the standard drug chloroquine diphosphate. Moreover, compounds 2a, 2b, 8a and 8b showed in vitro IC₅₀ values lower (p < 0.05) than that of the standard drug chloroquine phosphate (0.188 ± 0.003 µM) using the RKL9 strain. Compound 8b was the most active with IC₅₀ of 0.033 ± 0.014 µM. Generally, among the tested compounds, those containing a free carboxylic acid functional group on the pyrazole ring were the most active and this finding was supported by the docking results performed for the active compounds. The acute toxicity studies of the active compounds revealed that they have a good safety profile.     

In vitro antiplasmodial and antimicrobial potential of Tagetes erecta roots

Context: Among strategies to combat malaria, the search for newer antimalarial compounds is a priority. Traditionally, Tagetes erecta Linn. (Compositae) has been used for the treatment of various diseases and ailments including malaria.

Objective: Five successive extracts (petroleum ether, chloroform, ethyl acetate, methanol and aqueous) of the roots of T. erecta and a new bithienyl compound, 2-hydroxymethyl-non-3-ynoic acid 2-[2,2']-bithiophenyl-5-ethyl ester from the roots of the plant, were evaluated for in vitro antiplasmodial activity against chloroquine sensitive and resistant strains of Plasmodium falciparum. The extracts were also tested for in vitro antimicrobial activity against seven microbial strains.

Materials and methods: The antiplasmodial screening was carried out using the schizont maturation inhibition assay. Preliminary antimicrobial screening was carried out using the agar well assay followed by determination of minimum inhibitory concentration (MIC) using two-fold serial dilutions.

Results: Among all the extracts tested, the ethyl acetate fraction exhibited significant antiplasmodial efficacy with the 50% inhibitory concentrations (IC₅₀) of 0.02 and 0.07?mg/mL against the chloroquine sensitive and resistant strains of Plasmodium falciparum respectively. The new bithienyl compound also showed significant schizonticidal activity against both chloroquine sensitive and resistant strains of Plasmodium falciparum with the IC₅₀ values of 0.01 and 0.02?mg/mL. Additionally, all extracts exhibited significant antimicrobial activity against three Gram-positive and two Gram-negative bacterial and two fungal strains with MIC values ranging between 12.5-100 µg/mL.

Discussion: The new bithienyl compound was profoundly able to arrest the ring stages of the malarial parasites thereby exerting its antiplasmodial effect.

Conclusion: The observations provide support for the ethnobotanical use of the plant.     

Synthesis and antimicrobial activity of new 2‐piperazin‐1‐yl‐N‐1,3‐thiazol‐2‐ylacetamides of cyclopenta[c]pyridines and pyrano[3,4‐c]pyridines

In this study, we report the synthesis and antimicrobial activity of some new disubstituted piperazines. Thus, 3‐chlorocyclopenta[c]pyridines and 6‐chloropyrano[3,4‐c]pyridine 1 under mild reaction conditions with piperazine gave the 3(6)‐piperazine‐substituted cyclopenta[c]pyridines and pyrano[3,4‐c]pyridine 2 . Furthermore, the latter, by alkylation with 2‐chloro‐N‐1,3‐thiazol‐2‐ylacetamide, led to the formation of the target compounds. The evaluation of the antibacterial activity revealed that 3k was the most potent compound. The most sensitive bacterium was found to be Listeria monocytogenes, whereas Staphylococcus aureus was the most resistant one. Three compounds, 3d , 3g , and 3k , were tested also against the following resistant strains: methicillin‐resistant S. aureus (MRSA), Escherichia coli, and Pseudomonas aeruginosa. All three compounds appeared to be more potent than ampicillin against MRSA. Moreover, compound 3d showed a better activity than the reference drug ampicillin against P. aeruginosa, whereas 3g was more efficient against E. coli. The best antifungal activity was observed again for compound 3k . The most resistant fungi appeared to be Aspergillus fumigatus, whereas Trichoderma viride seemed the most sensitive one toward the compounds tested. Molecular docking studies on E. coli MurB, as well as on Candida albicans CYP51 and dihydrofolate reductase, were used for the prediction of the mechanisms of the antibacterial and antifungal activities, confirming the experimental results.     

Synergy Potential of Indole Alkaloids and Its Derivative against Drug‐resistant Escherichia coli

Antibacterial and synergy potential of naturally occurring indole alkaloids (IA): 10‐methoxy tetrahydroalstonine ( 1 ), isoreserpiline ( 2 ), 10 and 11 demethoxyreserpiline ( 3 ), reserpiline ( 4 ), serpentine ( 5 ), ajmaline ( 6 ), ajmalicine ( 7 ), yohimbine ( 8 ), and α ‐yohimbine ( 9 ) was evaluated using microbroth dilution assay. Further, α ‐yohimbine ( 9 ) was chemically transformed into six semisynthetic derivatives ( 9A‐9F ), and their antibacterial and synergy potential in combination with nalidixic acid (NAL) against E. coli strains CA8000 and DH5α were also evaluated. The IA 1 , 2 , 4 , 5 , 9 and the derivative 9F showed eightfold reduction in the MIC of NAL against the DH5 α and four‐ to eightfold reduction against CA8000. These alkaloids also reduced MIC of another antibiotic, tetracycline up to 8folds, against the MDREC‐KG4, a multidrug‐resistant clinical isolate of E. coli. Mode of action study of these alkaloids showed efflux pumps inhibitory potential, which was supported by their in silico binding affinity and downregulation of efflux pump genes. These results may be of great help in the development of cost‐effective antibacterial combinations for treating patients infected with multidrug‐resistant Gram‐negative infections.