Compounds 4o Research Articles

Targeting Mycobacterium tuberculosis: Synthesis, in vitro and in silico evaluation of novel N1 -(benzo[d]oxazol-2-yl)-N4 -arylidine compounds.

The development of novel antimycobacterial agents is an urgent challenge to eradicate the increasing emergence and rapid spread of multidrug-resistant strains. Filamentous temperature-sensitive protein Z (FtsZ) is a crucial cell division protein. Alteration of FtsZ assembly leads to cell division inhibition and cell death. To find novel antimycobacterial agents, a series of N1 -(benzo[d]oxazol-2-yl)-N4 -arylidine compounds 5a-o were synthesized. The activity of the compounds was evaluated against drug-sensitive, multidrug-resistant, and extensive-drug-resistant Mycobacterium tuberculosis. Compounds 5b, 5c, 5l, 5m, and 5o showed promising antimycobacterial activity with minimum inhibitory concentrations (MIC) in the range of 0.48-1.85 µg/mL and with low cytotoxicity against human nontumorigenic lung fibroblast WI-38 cells. The activity of the compounds 5b, 5c, 5l, 5m, and 5o was evaluated against bronchitis causing-bacteria. They exhibited good activity against Streptococcus pneumoniae, Klebsiella pneumoniae, Mycoplasma pneumonia, and Bordetella pertussis. Molecular dynamics simulations of Mtb FtsZ protein-ligand complexes identified the interdomain site as the binding site and key interactions. ADME prediction indicated that the synthesized compounds have drug-likeness. The density function theory studies of 5c, 5l, and 5n were performed to investigate E/Z isomerization. Compounds 5c and 5l are present as E-isomers and 5n as an E/Z mixture. Our experimental outcomes provide an auspicious lead for the design of more selective and potent antimycobacterial drugs.

Design, synthesis, and anticancer activity of novel 4,6-dimorpholinyl-1,3,5-triazine compounds

Abstract A series of novel 4,6-dimorpholinyl-1,3,5-triazine derivatives 6a–6r were obtained through N-substitution and Claisen-Schmidt condensation. 1H NMR, 13C NMR, and mass spectrometry were used to characterize the molecular structures of the derivatives. The in vitro antiproliferation activity of derivatives was evaluated using the MTT assay against SW620 (human colon cancer cells), A549 (human nonsmall cell lung cancer cells), HeLa (human cervical cancer cells), and MCF-7 (human breast cancer cells). Compound 6o bearing a pyridyl group exhibited good cytotoxicity against four cancer cells, with IC50 values of 8.71, 9.55, 15.67, and 21.77 μM, sequentially. In addition, compound 6a showed some selectivity against SW620.

Design, Synthesis and Antitumor Activity of 1H-indazole-3-amine Derivatives.

A series of indazole derivatives were designed and synthesized by molecular hybridization strategy, and these compounds were evaluated the inhibitory activities against human cancer cell lines of lung (A549), chronic myeloid leukemia (K562), prostate (PC-3), and hepatoma (Hep-G2) by methyl thiazolyl tetrazolium (MTT) colorimetric assay. Among these, compound 6o exhibited a promising inhibitory effect against the K562 cell line with the IC50 (50% inhibition concentration) value of 5.15 µM, and this compound showed great selectivity for normal cell (HEK-293, IC50 = 33.2 µM). Moreover, compound 6o was confirmed to affect apoptosis and cell cycle possibly by inhibiting Bcl2 family members and the p53/MDM2 pathway in a concentration-dependent manner. Overall, this study indicates that compound 6o could be a promising scaffold to develop an effective and low-toxic anticancer agent.

Synthesis of new multitarget-directed ligands containing thienopyrimidine nucleus for inhibition of 15-lipoxygenase, cyclooxygenases, and pro-inflammatory cytokines

A new series of thieno[2,3-d]pyrimidine derivatives 4, 5, 6a-o, and 11 was designed and synthesized starting from cyclohexanone under Gewald condition with the aim to develop multitarget-directed ligands (MTDLs) having anti-inflammatory properties against both 15-LOX and COX-2 enzymes. Moreover, the potential of the compounds against the proinflammatory mediators NO, ROS, TNF-α, and IL-6 were tested in LPS-activated RAW 264.7 macrophages. Compound 6o showed the greatest 15-LOX inhibitory effect (IC50 = 1.17 μM) which was superior to that of the reference nordihydroguaiaretic acid (NDGA, IC50 = 1.28 μM); meanwhile, compounds 6h, 6g, 11, and 4 exhibited potent activities (IC50 = 1.29–1.77 μM). The ester 4 (SI = 137.37) and the phenyl-substituted acetohydrazide 11 (SI = 132.26) showed the highest COX-2 selectivity, which was about 28 times more selective than the reference drug diclofenac (SI = 4.73), however, it was lower than that of celecoxib (SI = 219.25). Interestingly, compound 6o, which showed the highest 15-LOX inhibitory activity and 5 times higher COX-2 selectivity than diclofenac, showed a greater poteny in reducing NO (IC50 = 7.77 μM) than both celecoxib (IC50 = 22.89 μM) and diclofenac (IC50 = 25.34), but comparable activity in inhibiting TNF-α (IC50 = 11.27) to diclofenac (IC50 = 10.45 μM). Similarly, compounds 11 and 6h were more potent in reducing TNF-α and IL6 levels than diclofenac, meanwhile, compound 4 reduced ROS, NO, IL6, and TNF-α levels with comparable potency to the reference drugs celecoxib and diclofenac. Furthermore, docking studies for our compounds within 15-LOX and COX-2 active sites revealed good agreement with the biological evaluations. The proposed compounds could be promising multi-targeted anti-inflammatory candidates to treat resistant inflammatory conditions.

Design, Synthesis and In Vitro Studies of 3-Amidocoumarins as Novel Antibiofilm Agents

Pseudomonas aeruginosa, a life-threatening bacteria listed as a priority pathogen by World Health Organization WHO, is known to cause severe nosocomial infections and fatality in immunocompromised individuals through its quorum sensing (QS) mediated biofilm formation. P. aeruginosa’s antibiotic-resistant biofilms are highly challenging to the existing antibiotic treatment options. There is an urgent clinical need to develop novel alternative therapeutic molecules such as antibiofilm and antiquorum sensing agents to counter the emergence of an unprecedented pace of antibiotic resistance of pathogens. In this context, a library of seventy 3-amidocoumarin derivatives was designed, and docking studies were performed against the P. aeruginosa LasR receptor using AutoDock 4.0. Based on docking results, a final series of sixteen 3-amidocoumarin derivatives (4a–p) were synthesized and evaluated for antibiofilm activity in vitro. Eight compounds significantly inhibited the formation of P. aeruginosa PAO1 biofilm. Compounds 4f, 4l and 4o showed maximum % inhibition in antibiotic-resistant P. aeruginosa PAO1 biofilm formation in the range of 80% to 86%. Further, the structure–activity relationship (SAR) studies revealed that the presence of electron-donating and bromo substituents at benzamido and coumarin moieties, respectively, effectively enhances the antibiofilm activity. In addition, the binding interactions between the synthesized compounds and active sites of the LasR QS receptor (Protein Data Bank Code: 2uv0) in P. aeruginosa were also investigated by molecular docking. The high binding affinities indicate that these compounds might be suitable for development into potent inhibitors of QS and biofilm disruptors.

Novel Matrine Derivatives as Potential Larvicidal Agents against Aedes albopictus: Synthesis, Biological Evaluation, and Mechanistic Analysis.

A large number of studies have shown that matrine (MA) possesses various pharmacological activities and is one of the few natural, plant-derived pesticides with the highest prospects for promotion and application. Fifty-eight MA derivatives were prepared, including 10 intermediates and 48 target compounds in 3 series, to develop novel mosquitocidal agents. Compounds 4b, 4e, 4f, 4m, 4n, 6e, 6k, 6m, and 6o showed good larvicidal activity against Aedes albopictus, which is both a highly aggressive mosquito and an important viral vector that can transmit a wide range of pathogens. Dipping methods and a bottle bioassay were used for insecticidal activity evaluation. The LC50 values of 4e, 4m, and 6m reached 147.65, 140.08, and 205.79 μg/mL, respectively, whereas the LC50 value of MA was 659.34 μg/mL. Structure-activity relationship analysis demonstrated that larvicidal activity could be improved by the unsaturated heterocyclic groups introduced into the carboxyl group after opening the D ring. The MA derivatives with oxidized N-1 lost their mosquitocidal activities, indicating that the bareness of N-1 is crucial to maintain their anti-mosquito activity. However, the activity was not greatly influenced by introducing a cyan group at C-6 or a benzene sulfonyl group at N-16. Additionally, compounds 4e and 4m exhibited good inhibitory activities against acetylcholinesterase with inhibitory rates of 59.12% and 54.30%, respectively, at a concentration of 250 μg/mL, whereas the inhibitory rate of MA was 9.88%. Therefore, the structural modification and mosquitocidal activity of MA and its derivatives obtained here pave the way for those seeking strong mosquitocidal agents of plant origin.

Systematic Study on Turpentine-Derived Amides from Natural Plant Monoterpenes as Potential Antifungal Candidates.

To overcome the high volatility, low aqueous solubility, and few definite action sites of monoterpenoid pesticides and improve their properties and effectiveness in the control of crop pathogenic fungi, herein, a series of natural turpentine-based amide derivatives exhibiting satisfactory antifungal activity were designed and synthesized. A systematic study was conducted on antifungal activity and the physiological and biochemical response of compounds 5o (EC50 = 1.139 μg/mL) and 5j (EC50 = 1.762 μg/mL) against Rhizoctonia solani. The effect of the target compound on the potential target-site succinate dehydrogenase was evaluated. The soluble concentrates of compounds 5o and 5j possessing good performance and control effects were prepared for practical application. To conduct a comprehensive analysis of the relationship between structural descriptors and activity, four representative title compounds were selected for theoretical calculation: 5o, 5j, 5k, and 5j. The binding mode of compound 5o and boscalid with succinate dehydrogenase was analyzed via molecular docking. This study provides a reference for the development of monoterpene pesticides with high efficiency, elucidated target sites, and the appropriate formula.

Synthesis and biological evaluation of 2-nitrocinnamaldehyde derived thiosemicarbazones as urease inhibitors

Hyperactivity of urease enzyme induces pathogenesis of peptic ulcers and gastritis. The excess of urease can be reduced by introducing various inhibitors. The risk of high urease content also partakes in agriculture field where it declines the environmental health. This alarming situation leads to the mandatory quest of such novel scaffolds that must work wonders in the field of medicinal chemistry. Consequently, we herein report a novel series of N4-substitution of cinnamaldehyde with thiosemicarbazones 3a-q as potential candidates for urease inhibition. These new N4-substituted thiosemicarbazones 3a-q of indistinct chemical scaffolds were characterized by advanced spectroscopic techniques, such as ESI-MS, 13CNMR, 1HNMR, and FTIR. All newly synthesized compounds showed significant urease inhibitions with IC50 values in range of 11.4 ± 0.23 to 80.6 ± 0.52 μM. Furthermore, kinetic studies of compound 3o displayed competitive type of inhibition with ki value 8.65 ± 0.37 µM. For analysis of structure‒activity relationship and interactions pattern of all compounds, molecular docking was used, which revealed excellent binding interactions of compounds with the active site residues, such as nickel atom coordination, π–cation, π–π interactions, and hydrogen bonding. Additionally, the predicted pharmacokinetics and drug-likeness of compounds suggest that these compounds have good pharmacokinetic and physicochemical properties, and these compounds follow rules of drug-likeness.

Parsing structural fragments of thiazolidin-4-one based α-amylase inhibitors: A combined approach employing in vitro colorimetric screening and GA-MLR based QSAR modelling supported by molecular docking, molecular dynamics simulation and ADMET studies

α-Amylase (EC.3.2.1.1) is a ubiquitous digestive endoamylase. The abrupt rise in blood glucose levels due to the hydrolysis of carbohydrates by α-amylase at a faster rate is one of the main reasons for type 2 diabetes. The inhibitors prevent the action of digestive enzymes, slowing the digestion of carbs and eventually assisting in the management of postprandial hyperglycemia. In the course of developing α-amylase inhibitors, we have screened 2-aryliminothiazolidin-4-one based analogs for their in vitro α-amylase inhibitory potential and employed various in silico approaches for the detailed exploration of the bioactivity. The DNSA bioassay revealed that compounds 5c, 5e, 5h, 5j, 5m, 5o and 5t were more potent than the reference drug (IC60 value = 22.94 ± 0.24 μg mL−1). The derivative 5o with –NO2 group at both the rings was the most potent analog with an IC60 value of 19.67 ± 0.20 μg mL−1 whereas derivative 5a with unsubstituted aromatic rings showed poor inhibitory potential with an IC60 value of 33.40 ± 0.15 μg mL−1. The reliable QSAR models were developed using the QSARINS software. The high value of R2ext = 0.9632 for model IM-9 showed that the built model can be applied to predict the α-amylase inhibitory activity of the untested molecules. A consensus modelling approach was also employed to test the reliability and robustness of the developed QSAR models. Molecular docking and molecular dynamics were employed to validate the bioassay results by studying the conformational changes and interaction mechanisms. A step further, these compounds also exhibited good ADMET characteristics and bioavailability when tested for in silico pharmacokinetics prediction parameters.

Design, synthesis, antifungal activity and molecular docking of ring-opened pimprinine derivative containing (thio)amide structure.

To obtain new environmentally friendly fungicides, we used the natural product pimprinine as the lead compound, and designed and synthesized two series of ring-opening derivatives of pimprinine containing amide/thioamide. We then studied their antifungal activity against six common plant pathogenic fungi in vitro. Most of the target compounds have good antifungal activity against six important plant pathogenic fungi in vitro. At a concentration of 50 μg ml-1 , compound 3o showed prominent antifungal effects on Alternaria solani and Rhioctornia solani, with inhibition rates of 91.8% and 97.4%, and a 50% effective concentration (EC50 ) of 6.2255 and 0.6969 μg ml-1 respectively. The EC50 of compound 3o against Alternaria solani was significantly lower than that of boscalid (13.0380 μg ml-1 ) and flutriafol (11.9057 μg ml-1 ). In addition, compound 3o had good antifungal activity against Sclerotinia sclerotiorum, cucumber powdery mildew, cucumber Botrytis cinerea and Phytophthora capsici in vivo; the antifungal activity of compound 3o against cucumber Botrytis cinerea is 91.7%. At the same time, docking results for highly active compound 3o with the presumed target succinate dehydrogenase and the molecular docking prediction scores of all compounds further indicate its possible antifungal activity mechanism. The designed and optimized derivative 3o of ring-opening pimprinine has good antifungal activity and can be used as a new antifungal drug for further research. © 2023 Society of Chemical Industry.

New benzimidazole-oxadiazole derivatives: Synthesis, α-glucosidase, α-amylase activity, and molecular modeling studies as potential antidiabetic agents.

Benzimidazole-1,3,4-oxadiazole derivatives (5a-z) were synthesized and characterized with different spectroscopic techniques such as 1 H NMR, 13 C NMR, and HRMS. The synthesized analogs were examined against α-glucosidase and α-amylase enzymes to determine their antidiabetic potential. Compounds 5g and 5q showed the most activity with 35.04 ± 1.28 and 47.60 ± 2.16 µg/mL when compared with the reference drug acarbose (IC50 = 54.63 ± 1.95 µg/mL). Compounds 5g, 5o, 5s, and 5x were screened against the α-amylase enzyme and were found to show excellent potential, with IC50 values ranging from 22.39 ± 1.40 to 32.07 ± 1.55 µg/mL, when compared with the standard acarbose (IC50 = 46.21 ± 1.49 µg/mL). The antioxidant activities of the effective compounds (5o, 5g, 5s, 5x, and 5q) were evaluated by TAS methods. A molecular docking research study was conducted to identify the active site and explain the functions of the active chemicals. To investigate the most likely binding mode of the substances 5g, 5o, 5q, 5s, and 5x, a molecular dynamics simulation was also carried out.

Design, Synthesis, and Fungicidal Evaluation of Novel N-Methoxy Pyrazole-4-Carboxamides as Potent Succinate Dehydrogenase Inhibitors.

Succinate dehydrogenase (SDH, EC 1.3.5.1, also known as complex II) has been recognized as one of the most promising targets of fungicides. Here, based on the binding mode of pydiflumetofen with SDH, the carbon-carbon double bond was introduced into the chemical of pydiflumetofen and then produced the target compounds 6a-6o. The enzymatic inhibitory activity and structure-activity relationship (SAR) study showed that the 2-position and 4-position in terminal benzene were positive to increasing activity. Furthermore, fungicidal activity results in greenhouses indicated that compound 6o showed good control effects against wheat powdery mildew (WPM), cucumber powdery mildew (CPM), and southern corn rust (SCR), showing its broad-spectrum property. Especially, compound 6o exhibited 95 and 75% control effects against CPM and SCR at 6.25 mg/L, respectively, which are better than pydiflumetofen (80% control effects against CPM and 15% against SCR), indicating its potency that is worthy of further development.

Novel quinolin-2(1H)-one analogues as potential fungicides targeting succinate dehydrogenase: design, synthesis, inhibitory evaluation and molecular modeling.

Succinate dehydrogenase is an important target of fungicides. Succinate dehydrogenase inhibitors (SDHIs) have widely been used to combat destructive plant pathogenic fungi because they possess efficient and broad-spectrum antifungal activities and as well as unique mode of action. The research and development of novel SDHIs have been ongoing. Thirty-six novel quinolin-2(1H)-one derivatives were designed, synthesized and characterized. The single crystal structure of compound 3c was determined through the X-ray diffraction of single crystals. The bioassay results displayed that most compounds had good antifungal activities at 16 μg mL-1 against Rhizoctonia cerealis, Erysiphe graminis, Botrytis cinerea, Penicillium italicum and Phytophthora infestans. Compounds 6o, 6p and 6r had better antifungal activities than the commercialized fungicide pyraziflumid against Botrytis cinerea. Their half maximal effective concentration (EC50 ) values were 0.398, 0.513, 0.205 and 0.706 μg mL-1 , respectively. Moreover, the inhibiting activities of the bioactive compounds were tested against succinate dehydrogenase. The results indicated that they possessed outstanding activities. Compounds 6o, 6p and 6r also exhibited better inhibiting activities than pyraziflumid against succinate dehydrogenase. Their half maximal inhibitory concentration (IC50 ) values were 0.450, 0.672, 0.232 and 0.858 μg mL-1 , respectively. The results of molecular dynamic (MD) simulations indicated that compound 6r displayed stronger affinity to succinate dehydrogenase than pyraziflumid. The results of the present study displayed that quinolin-2(1H)-one derivative could be one scaffold of potential SDHIs and will provide some valuable information for the research and development of new SDHIs. © 2022 Society of Chemical Industry.

Design, Synthesis and Molecular Docking Studies of (S)-1-(2-(substituted benzylamino)-3- methylbutanoyl)pyrrolidin-2-one analogues as GABA Mediated Anticonvulsant agents

Abstract: Background: Epilepsy is a deep rooted, partially curable brain illness that affects all individuals irrespective of ages and genders. Despite the discovery of various innovative antiepileptic drugs (AEDs), selectivity and toxicity issues remain. Materials and Methods: A series of (S)-1-(2-(substituted benzylamino)-3-methylbutanoyl)pyrrolidin-2-one analogues (5a-r) were synthesized and evaluated for their anticonvulsant activity. The analogues were screened by two gold standard methods, i.e., electroshock (MES) and chemoshock (scPTZ) seizure tests. In addition, the rotarod method was used to test motor impairment in all synthetic analogues for acute neurotoxicity. The paper also reports ADME prediction of all the 18 synthesized compounds, with each parameter discussed in detail. Furthermore, the GABA-A target protein was used in molecular docking experiments. Results: In the MES model, compounds 5e, 5h, 5k, 5l, 5o, and 5r were identified to be the most effective, while compounds 5j, 5k, 5l, 5o, and 5r were the most active against the scPTZ model. The majority of the synthesized analogues passed the neurotoxicity test, according to the findings. ADME prediction of the compounds exhibited good agreement with the in vivo outcomes. The results of molecular docking showed important interactions with TYR 62, ASN 85, ARG 114, ARG 129, and MET 115 at the active site of GABA-A and the results showed good agreement with in vivo results. Conclusion: The findings of the study indicated some of the compounds possessed excellent anticonvulsant activity without noticeable neurotoxicity. These compounds can be investigated further for the formation of newer/novel anticonvulsant agents. Keywords: Pyrrolidine, Anticonvulsant activity, Molecular Docking, GABA-A, Toxicity, ADME prediction.

New thioxothiazolidinyl-acetamides derivatives as potent urease inhibitors: design, synthesis, in vitro inhibition, and molecular dynamic simulation

To identify potent urease inhibitors, in the current study, a series of thioxothiazolidinyl-acetamides were designed and synthesized. The prepared compounds were characterized by spectroscopic techniques, including FTIR, 1HNMR, 13CNMR, and elemental analysis. In the enzymatic assessments, it was demonstrated that all derivatives had significant urease inhibition with IC50 values in the range of 1.473–9.274 µM in comparison with the positive control hydroxyurea (IC50 = 100.21 ± 2.5 µM) and thiourea (IC50 = 23.62 ± 0.84 µM). Compound 6i (N-benzyl-3-butyl-4-oxo-2-thioxothiazolidine-5-carboxamide) was the most active agent with an IC50 value of 1.473 µM. Additionally, kinetic investigation and in silico assessments of 6i was carried out to understand the type of inhibition and behavior of the most potent derivative within the binding site of the enzyme. Noteworthy, the anti-urease assay against P. vulgaris revealed 6e and 6i as the most active agents with IC50 values of 15.27 ± 2.40 and 17.78 ± 3.75 µg/mL, respectively. Antimicrobial evaluations of all compounds reveal that compounds 6n and 6o were the most potent antimicrobial agents against the standard and resistant S. aureus. 6n and 6o also showed 37 and 27% inhibition in the development of biofilm by S. aureus at 512 µg/ml. Furthermore, the MTT test showed no toxicity up to 100 µM. Taken together, the study suggests that the synthesized thioxothiazolidinyl-acetamides bases derivatives may serve as potential hits as urease inhibitors.

Pyrrolizine/indolizine-bearing (un)substituted isoindole moiety: design, synthesis, antiproliferative and MDR reversal activities, and in silico studies.

Two new series of pyrrolizine/indolizine derivative-bearing (un)substituted isoindole moiety were designed and synthesized. The anticancer potential of the new compounds was evaluated against hepatocellular carcinoma (HepG-2), colorectal carcinoma, colon cancer (HCT-116), and breast cancer (MCF-7) cell lines. Compounds 6d and 6o were the most potent derivatives with IC50 values ranging from 6.02 to 13.87 μM against HePG-2, HCT-116, and MCF-7 cell lines. Moreover, methyl analog of the fluoro-substituted indolizine derivative 6m revealed significant antiproliferative activity against HePG-2, HCT-116, and MCF-7 cancer cell lines with IC50 values of 11.97, 28.37, and 19.87 μM, respectively. The most active anticancer analogs, 6d, 6m, and 6o, were inspected for their putative mechanism of action by estimating their epidermal growth factor receptor (EGFR) and cyclin-dependent kinase (CDK 2) inhibitory activities. Thus, compound 6o displayed the most inhibitory activity against EGFR and CDK 2 with IC50 values of 62 and 118 nM, respectively. Additionally, the quantitative real-time PCR analysis for the P-glycoprotein effect of compounds 6d, 6m, and 6o was performed, in which compound 6o illustrated significant down-regulation of P-gp against the HepG-2 cell line by 0.2732 fold. Mechanistic studies for the most active compounds involving the reversal doxorubicin (DOX) effect of compounds 6d, 6m, and 6o were performed, which illustrated cytotoxic activity with IC50 22.27, 3.88, and 8.79 μM, respectively. Moreover, the apoptotic activity of the most active derivative 6o on HCT-116 cancer cells showed accumulation in the G1 and S phases of the cell cycle.

Expanding the scope of novel 1,2,3-triazole derivatives as new antiparasitic drug candidates.

We have previously shown that prenyl and aliphatic triazoles are interesting motifs to prepare new chemical entities for antiparasitic and antituberculosis drug development. In this opportunity a new series of prenyl-1,2,3-triazoles were prepared from isoprenyl azides and different alkynes looking for new antimalarial drug candidates. The compounds were prepared by copper(i) catalyzed dipolar cycloaddition of the isoprenyl azide equilibrium mixture providing exclusively 1,4-disubstituted 1,2,3-triazoles in a regiospecific fashion. The complete collection of 64 compounds was tested on chloroquine-sensitive (CQ sensitive), Sierra Leone (D6), and the chloroquine-resistant, Indochina (W2), strains of Plasmodium falciparum and those compounds which were not previously reported were also tested against Leishmania donovani, the causative agent for visceral leishmaniasis. Thirteen analogs displayed antimalarial activity with IC50 below 10 μM, while the antileishmanial activity of the newly reported analogs could not improve upon those previously reported. Compounds 1o and 1r were identified as the most promising antimalarial drug leads with IC50 below 3.0 μM for both CQ-sensitive and resistant P. falciparum strains with high selectivity index. Finally, a chemoinformatic in silico analysis was performed to evaluate physicochemical parameters, cytotoxicity risk and drug score. The validation of a bifunctional farnesyl/geranylgeranyl diphosphate synthase PfFPPS/GGPPS as the potential target of the antimalarial activity of selected analogs should be further investigated.

New nitazoxanide derivatives: design, synthesis, biological evaluation, and molecular docking studies as antibacterial and antimycobacterial agents.

A new series inspired by combining fragments from nitazoxanide (NTZ) and 4-aminosalicylic acid (4-ASA) was synthesized and screened for in vitro antibacterial and antimycobacterial activities. The majority showed higher antibacterial potency than NTZ against all the screened strains, notably, 5f, 5j, 5n and 5o with MICs of 0.87-9.00 μM. Compounds 5c, 5n and 5o revealed higher potency than ciprofloxacin against K. pneumoniae, while 5i was equipotent. For E. faecalis, 3b, 5j, and 5k showed higher potency than ciprofloxacin. 5j was more potent against P. aeruginosa than ciprofloxacin, while 5n was more potent against S. aureus with an MIC of 0.87 μM. 5f showed equipotency to ciprofloxacin against H. pylori with an MIC of 1.74 μM. Compounds 3a and 3b (4-azidoNTZ, MIC 4.47 μM) are 2 and 5-fold more potent against Mycobacterium tuberculosis (Mtb H37Rv) than NTZ (MIC 20.23 μM) and safer. 4-Azidation and/or acetylation of NTZ improve both activities, while introducing 1,2,3-triazoles improves the antibacterial activity. Molecular docking studies within pyruvate ferredoxin oxidoreductase (PFOR), glucosamine-6-phosphate synthase (G6PS) and dihydrofolate reductase (DHFR) active sites were performed to explore the possible molecular mechanisms of actions. Acceptable drug-likeness properties were found. This study may shed light on further rational design of substituted NTZ as broad-spectrum more potent antimicrobial candidates.

Discovery of pyrrole derivatives as acetylcholinesterase-sparing butyrylcholinesterase inhibitor.

Inspired by the crucial roles of (hetero)aryl rings in cholinesterase inhibitors and the pyrrole ring in new drug discovery, we synthesized 19 pyrrole derivatives and investigated their cholinesterase inhibitory activity. As a result, compounds 3o, 3p, and 3s with a 1,3-diaryl-pyrrole skeleton showed high selectivity toward BChE over AChE with a best IC50 value of 1.71 ± 0.087µM, which were comparable to donepezil. The pharmaceutical potential of these structures was further predicted and compounds 3o and 3p were proved to meet well with the Lipinsky's five rules. In combination of the inhibition kinetic studies with the results of molecular docking, we concluded that compound 3p inhibited BChE in a mixed competitive mode. This research has proved the potential of the 1,3-diaryl-pyrrole skeleton as a kind of selective BChE inhibitor.

Synthesis and in vitro antibacterial, antifungal, anti-proliferative activities of novel adamantane-containing thiazole compounds

A series of (Z)-N-(adamantan-1-yl)-3,4-diarylthiazol-2(3H)-imines (5a-r) was synthesized via condensation of 1-(adamantan-1-yl)-3-arylthioureas (3a-c) with various aryl bromomethyl ketones (4a-f). The structures of the synthesized compounds were characterized by 1H NMR, 13C NMR and by X-ray crystallography. The in vitro inhibitory activities of the synthesized compounds were assessed against a panel of Gram-positive and Gram-negative bacteria, and pathogenic fungi. Compounds 5c, 5g, 5l, 5m, and 5q displayed potent broad-spectrum antibacterial activity, while compounds 5a and 5o showed activity against the tested Gram-positive bacteria. Compounds 5b, 5l and 5q displayed potent antifungal activity against Candida albicans. In addition, the synthesized compounds were evaluated for anti-proliferative activity towards five human tumor cell lines. The optimal anti-proliferative activity was attained by compounds 5e and 5k which showed potent inhibitory activity against all the tested cell lines. Molecular docking analysis reveals that compounds 5e and 5k can occupy the positions of NAD cofactor and the histone deacetylase inhibitor EX527 at the active site of SIRT1 enzyme.