Compounds 4o Research Articles

Trifluoromethylcinnamanilide Michael Acceptors for Treatment of Resistant Bacterial Infections

A series of thirty-two anilides of 3-(trifluoromethyl)cinnamic acid (series 1) and 4-(trifluoromethyl)cinnamic acid (series 2) was prepared by microwave-assisted synthesis. All the compounds were tested against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 and resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis (VRE). All the compounds were evaluated in vitro against Mycobacterium smegmatis ATCC 700084 and M. marinum CAMP 5644. (2E)-3-[3-(Trifluoromethyl)phenyl]-N-[4-(trifluoromethyl)phenyl]prop-2-enamide (1j), (2E)-N-(3,5-dichlorophenyl)-3-[3-(trifluoromethyl)phenyl]prop-2-enamide (1o) and (2E)-N-[3-(trifluoromethyl)phenyl]-3-[4-(trifluoromethyl)-phenyl]prop-2-enamide (2i), (2E)-N-[3,5-bis(trifluoromethyl)phenyl]-3-[4-(trifluoromethyl)phenyl]-prop-2-enamide (2p) showed antistaphylococcal (MICs/MBCs 0.15-5.57 µM) as well as anti-enterococcal (MICs/MBCs 2.34-44.5 µM) activity. The growth of M. marinum was strongly inhibited by compounds 1j and 2p in a MIC range from 0.29 to 2.34 µM, while all the agents of series 1 showed activity against M. smegnatis (MICs ranged from 9.36 to 51.7 µM). The performed docking study demonstrated the ability of the compounds to bind to the active site of the mycobacterial enzyme InhA. The compounds had a significant effect on the inhibition of bacterial respiration, as demonstrated by the MTT assay. The compounds showed not only bacteriostatic activity but also bactericidal activity. Preliminary in vitro cytotoxicity screening was assessed using the human monocytic leukemia cell line THP-1 and, except for compound 2p, all effective agents did show insignificant cytotoxic effect. Compound 2p is an interesting anti-invasive agent with dual (cytotoxic and antibacterial) activity, while compounds 1j and 1o are the most interesting purely antibacterial compounds within the prepared molecules.

Synthesis of new 3-(4-methyl-2-arylthiazol-5-yl)-5-aryl-1,2,4-oxadiazole derivatives as potential cytotoxic and antimicrobial agents

Globally cancer is the second leading cause of death; a drug that can cure cancer with the utmost negligible side effects is still a distant goal. Due to increasing antibiotic resistance, microbial infection remains a grave global health security threat. The ongoing coronavirus pandemic increased the risk of microbial and fungal infection. A new series of 3-(4-methyl-2-arylthiazol-5-yl)-5-aryl-1,2,4-oxadiazole (7a-t) have been synthesized. The structure of synthesized compounds was confirmed by the spectrometric analysis. The newly synthesized compounds were screened for cytotoxic activity against breast cell lines MCF-7 and MDA-MB-231. Against the MCF-7 ​cell line compounds 7f, 7 ​g and 7n showed excellent activity with GI50 0.6 ​μM to <100 ​nM concentration. Compound 7b showed good activity against MDA-MB-231 ​cell line with GI50 47 ​μM. The active derivatives 7b, 7e, 7f, 7 ​g and 7n were further evaluated for cytotoxicity against the epithelial cell line derived from the human embryonic kidney (HEK 293) and were found nontoxic. The thiazolyl-1,2,4-oxadiazole derivatives were also screened to evaluate theirs in vitro antimicrobial potential against Escherichia coli (NCIM 2574), Proteus mirabilis (NCIM 2388), Bacillus subtilis (NCIM 2063), Staphylococcus albus (NCIM 2178), Candida albicans (NCIM 3100) and Aspergillus niger (ATCC 504). Amongst the 7a-t derivatives, six compounds 7a, 7d, 7f, 7n, 7o, 7r showed good antifungal activity against C. albicans and eight compounds 7c, 7d, 7 ​g, 7h, 7i, 7k, 7l and 7o showed good activity against A. niger. The potential cytotoxic and antifungal activity suggested that the thiazolyl-1,2,4-oxadiazole derivatives could assist in the development of lead compounds for the treatment of cancer and microbial infections.

Lupane derivatives containing various aryl substituents in the position 3 have selective cytostatic effect in leukemic cancer cells including resistant phenotypes

In this work, a large set of betulinic acid derivatives modified with various aromatic substituents at the position C-3 were prepared via Suzuki-Myiaura cross-coupling. All compounds were tested for their in vitro cytotoxic activity in 8 cancer and 2 healthy cell lines. Derivatives 6h, 6i, and 6o had the lowest IC50 in the CCRF-CEM cell line (0.69–4.0 μM) and had high selectivity. In addition, 6h and 6i also showed significant activity in daunorubicin-resistant CEM and taxol-resistant K562 cell lines; therefore, they were selected for the evaluation of the mechanism of action. First, the effect of 6h, 6i, and 6o on cell death induction was studied. To our surprise, we have not detected almost any apoptotic cells, even following a long-time exposure of CCRF-CEM cells to the compounds. On the other hand, a dramatic cell number decrease was observed, proportional to the time of the compound's exposure. Based on this data it was concluded that the effect of compounds is cytostatic rather than cytotoxic, which was further confirmed by subsequent studies of the impact of 6h, 6i, and 6o on the cell cycle. Detailed cell cycle analysis revealed a block in the G1 phase accompanied by reduced expression of phosphorylated forms of the RB protein as well as cyclin A protein. Evaluation of the pharmacological properties of the most promising compounds revealed their high stability in the presence of phosphate buffer, human plasma, and microsomes and limited permeability determined using permeability through artificial membrane (PAMPA) and cell permeability assay: Caco-2 and MDCK-MDR1 cell lines. Compounds 6h, 6i, and 6o were selected for further drug development; their cytostatic effect may be advantageous in this process since we expect fewer non-specific interactions and toxicity than in highly cytotoxic compounds. In addition, the activity of 6h and 6i against resistant CEM-DNR and K562-TAX leukemic cell lines makes them promising as a possible future alternative to currently used therapies.

Synthesis and biological evaluation of coumarin-thiazole hybrids as selective carbonic anhydrase IX and XII inhibitors.

A series of coumarin-linked thiazoles (6a-p) was synthesized and the synthesized compounds were evaluated against human carbonic anhydrases (hCAs) IX and XII, which have been implicated in cancer. All the compounds exhibited selective inhibition of both isoforms. The designed compounds inhibited hCA IX in a moderate nanomolar to submicromolar range. The hCA XII was inhibited in a low to moderate nanomolar range. Compound 6o exhibited the best inhibition of hCA XII with a Ki value of 91.1 nM. The hydrolyzed form of compound 6o also exhibited favorable interactions as well as good docking scores with both the isoforms. Hence, this compound can be taken as a template for the design of selective and potent hCA XII inhibitors.

Bacterial FtsZ inhibition by benzo[d]imidazole-2-carboxamide derivative with anti-TB activity.

Aims: The present study aimed to assess the mode of action of previously reported anti-Mycobacterium tuberculosis benzo[d]imidazole-2-carboxamides against FtsZ along with their antibacterial potential. Materials & methods: The anti-mycobacterial action of benzo[d]imidazole-2-carboxamides against FtsZ was evaluated using inhibition of Bacillus subtilis 168, light scattering assay, circular dichroism spectroscopy, in silico molecular docking and molecular dynamics simulations. Results & conclusion: Three compounds (1k, 1o and 1e) were active against isoniazid-resistant strains. Four compounds (1h, 1i, 1o and 4h) showed >70% inhibition against B. subtilis 168. Compound 1o was the most potent inhibitor (91±5% inhibition) ofB. subtilis 168 FtsZ and perturbed its secondary structure. Molecular docking and molecular dynamics simulation of complexed 1o suggested M. tuberculosis FtsZ as a possible target for antitubercular activity.

Assessing p-tolyloxy-1,3,4-oxadiazole acetamides as lipoxygenase inhibitors assisted by in vitro and in silico studies

The underlying correlation between the inflammation, innate immunity and cancer is extensively familiar and linked through a process mediated by three enzymes; cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP450). The ever increase in the reported side effects of the antiinflammatory drugs against the targeted enzymes and the resistance developed afterwards compels the researchers to synthesize new effective molecules with safer profile. On the basis of these facts, our ongoing research on 1,3,4-oxadiazole derivatives deals with the synthesis of a new series of N-alkyl/aralky/aryl derivatives of 5-((p-tolyloxymethyl)-4H-1,3,4-oxadiazole-2-ylthio)acetamide (6a-o) which were developed by the sequential conversion of p-tolyloxyacetic acid (a) into ester (1) hydrazide (2) and 5-(p-tolyloxymethyl)-4H-1,3,4-oxadiazole-2-thiol (3). The designed compounds (6a-o) were acquired by the reaction of 1,3,4-oxadiazole (3) with numerous electrophiles (5a-o) in KOH. The synthesized analogues (6a-o) were characterized by FTIR, 1H-, 13C NMR spectroscopy, EI-MS and HR-EI-MS spectrometry, and were further assessed for their inhibitory potential against the soybean 15-LOX enzyme. The results showed excellent inhibitory potential of the compounds against the said enzyme, specifically 6o, 6b, 6n and 6e with inhibitory values (IC50 ± SEM) of 21.5 ± 0.76, 24.3 ± 0.45, 29.1 ± 0.65 and 31.3 ± 0.78 µM, respectively. These compounds displayed < 55 % blood mononuclear cells (MNCs) cellular viability as measured by MTT assay at 0.25 mM concentration. Other compounds demonstrated moderate inhibitory activities with IC50 values in the range of 33.2 ± 0.78 to 96.3 ± 0.73 µM and exhibited little cellular viability against MNCs except 6i, 6j, 6 m and 6 k that showed 61–79 % cellular viability. It was observed that most of the compounds (6o, 6b, 6n, 6e) were found more toxic towards MNCs at studied concentration of 0.25 mM. SAR studies revealed that the positions and nature of substituents accompanying phenyl ring have great influence on 15-LOX inhibitory activity. In the most active compound 6o, the amino acids Asp768 and Val126 were involved in hydrogen bonding, Thr529 was linked with π-anion interaction and π-sulphur interaction was displayed with Tyr525 and two π-alkyl interactions were formed with the benzene ring and amino acid residues Pro530 and Arg533. The in silico pharmacokinetics profiles and density functional theory calculations of the compounds further supported the in vitro findings. Further work on the synthesis of more oxadiazole derivatives is in progress in search for potential ‘leads’ for the drug discovery as LOX inhibitors.

Identification of Novel Aryl Carboxamide Derivatives as Death-Associated Protein Kinase 1 (DAPK1) Inhibitors with Anti-Proliferative Activities: Design, Synthesis, In Vitro, and In Silico Biological Studies.

Death-associated protein kinase 1 (DAPK1) is a serine/threonine protein kinase involved in diverse fundamental cellular processes such as apoptosis and autophagy. DAPK1 isoform plays an essential role as a tumor suppressor and inhibitor of metastasis. Consequently, DAPK1 became a promising target protein for developing new anti-cancer agents. In this work, we present the rational design and complete synthetic routes of a novel series of eighteen aryl carboxamide derivatives as potential DAPK1 inhibitors. Using a custom panel of forty-five kinases, a single dose of 10 µM of the picolinamide derivative 4a was able to selectively inhibit DAPK1 kinase by 44.19%. Further investigations revealed the isonicotinamide derivative 4q as a promising DAPK1 inhibitory lead compound with an IC50 value of 1.09 µM. In an in vitro anticancer activity assay using a library of 60 cancer cell lines including blood, lung, colon, CNS, skin, ovary, renal, prostate, and breast cancers, four compounds (4d, 4e, 4o, and 4p) demonstrated high anti-proliferative activity with mean % GI ~70%. Furthermore, the most potent DAPK1 inhibitor (4q) exhibited remarkable activity against leukemia (K-562) and breast cancer (MDA-MB-468) with % GI of 72% and 75%, respectively.

Synthesis of Sulfonamides Incorporating Piperidinyl-Hydrazidoureido and Piperidinyl-Hydrazidothioureido Moieties and Their Carbonic Anhydrase I, II, IX and XII Inhibitory Activity.

Here we report a small library of hydrazinocarbonyl-ureido and thioureido benzenesulfonamide derivatives, designed and synthesized as potent and selective human carbonic anhydrase inhibitors (hCAIs). The synthesized compounds were evaluated against isoforms hCA I, II, IX and XII using acetazolamide (AAZ) as standard inhibitor. Several urea and thiourea derivatives showed inhibitory activity at low nanomolar levels with selectivity against the cytosolic hCA II isoform, as well as the transmembrane, tumor-associated enzymes hCA IX and XII. The thiourea derivatives showed enhanced potency as compared to urea analogues. Additionally, eight compounds 5g, 5m, 5o, 5q, 6l, 6j, 6o and 6u were selected for docking analysis on isoform I, II, IX, XII to illustrate the potential interaction with the enzyme to better understand the activity against the different isoforms.

Novel [1,2,4]-Triazolo[3,4-b]-[1,3,4]thiadizoles as Potent Pyruvate Kinase Inhibitors for Fungal Control.

To discover novel target-based fungicidal candidates, a molecular design model was established with a three-dimensional (3D) structure of Rhizoctonia solani pyruvate kinase (RsPK) simulated with the AlphaFold 2 and YZK-C22 as a fungicidal lead. A series of novel [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives were rationally designed, synthesized, evaluated for their fungicidal performance, and validated for their mode of action. The in vitro bioassays with R. solani indicated that compounds 5g, 5o, and 5z with an EC50 value ranging from 1.01 to 1.54 μg/mL displayed higher fungicidal activity than the positive control YZK-C22 with its EC50 of 3.14 μg/mL. Especially, 5o exhibited high potency and a broad spectrum against Alternaria solani, Botrytis cinerea, Cercospora arachidicola, Physalospora piricola, R. solani, and Sclerotinia sclerotiorum with its EC50 value falling between 1.54 and 13.10 μg/mL. Like all positive controls, 5g, 5o, and 5z showed excellent in vivo growth inhibition against Pseudoperonospora cubensis at 200 μg/mL. Even though the PK enzymatic inhibition assay showed that 5o was approximately 2.6 times less active than YZK-C22 (IC50: 29.14 vs 11.15 μg/mL, respectively), the similar fluorescence quenching patterns of RsPK by 5o and YZK-C22, and the docking results of interactions between RsPK and 5o or YZK-C22 implied that they might share the similar binding site in the RsPK active pocket. Our studies suggested that 5o could be used as a potent fungicidal lead for further optimization. The results of comparative molecular field analysis (CoMFA) provided a direction for further molecular design.

Convenient synthesis of benzothiazinoisoindol-11-ones and benzoindenothiazin-11-ones, and antimicrobial testing thereof.

Benzo[5,6][1,4]thiazino[3,4-a]isoindol-11-ones 5a-t and benzo[b]indeno[1,2-e][1,4]thiazin-11(10aH)-ones 6a-e were synthesized conveniently via cyclocondensation of 2-bromo-2-(2/3-substitutedphenyl)-1H-indene-1,3(2H)-diones and 2-aminobenzenethiols in freshly dried ethanol with 70-85% yields. The synthesized derivatives were well characterized by employing different spectral techniques (FTIR, 1H & 13C NMR and HRMS) and X-ray crystallographic analysis. Further, all the reported compounds were tested for their antibacterial and antifungal activities using Ciprofloxacin and Fluconazole as standard drugs, respectively. The results of antimicrobial evaluation revealed that compounds 5o and 5t displayed remarkable inhibitory activity against B. subtilis, S. aureus, P. aeruginosa and A. niger with MIC values in the range of 0.0141-0.0283µmol/mL, whereas 5j was found active against E. coli and C. albicans with MIC values of 0.0286µmol/mL and 0.0143µmol/mL, respectively. Additionally, among all the benzo[b]indeno[1,2-e][1,4]thiazin-11(10aH)-ones, 6c exhibited excellent inhibition against all the tested bacterial and fungal strains with MIC values ranging from 0.0143 to 0.1145µmol/mL. Structure activity relationships were also established for all the tested benzo[5,6][1,4]thiazino[3,4-a]isoindol-11-ones 5a-t.

Synthesis, molecular docking and enzyme inhibitory approaches of some new chalcones engrafted pyrazole as potential antialzheimer, antidiabetic and antioxidant agents

About 25 chalcones engrafted pyrazole scaffold combined with benzothiophene and indole moieties 5a-y were designed and constructed in two steps using readily available acetyl acetone, phenyl hydrazine and DMF-DMA as starting material. The synthesized chalcone analogs were screened for in vitro anti-acetylcholinesterase potential, antidiabetic potential against α-glucosidase and α-amylase, and antioxidant potentials against DPPH free radicals. The compounds 5a, 5r, 5m, 5o and 5p showed strongest acetylcholine esterase inhibition (AChEI) with IC50 values of 5 ± 1.16 μg/mL (5p), 8 ± 0.14 μg/mL (5a), 8 ± 0.57 μg/mL (5r), 10 ± 1.73 μg/mL (5m) and 10 ± 0.60 μg/mL (5o). The highest inhibition against α-glucosidase was demonstrated by compounds 5f, 5o, 5j, 5e, 5c, and 5a with IC50 values of 4 ± 0.14, 6 ± 0.43, 8 ± 0.43, 10 ± 0.11, 11 ± 0.28 and 12 ± 0.57 μg/mL respectively, whereas, the compounds 5x, 5d, 5w, 5y and 5u showed prominent α-amylase inhibition with IC50 values of 20 ± 1.15 μg/mL (5x), 30 ± 0.60 μg/mL (5d), 40 ± 0.72 μg/mL (5w), 40 ± 0.50 μg/mL (5y), and 60 ± 2.19 μg/mL (5u). The highest anti-oxidant potential against DPPH free radicals was demonstrated by compounds 5w, 5v and 5y with IC50 values of 160 ± 5.77, 260 ± 4.63, and 360 ± 4.04 μg/mL respectively. Molecular docking was used to study their interaction with the active site of enzymes.

Synthesis, in Vitro Cholinesterase Inhibition, Molecular Docking, DFT, and ADME Studies of Novel 1,3,4-Oxadiazole-2-Thiol Derivatives.

A series of 1,3,4-oxadiazole-2-thiol derivatives bearing various alkyl or aryl moieties were designed, synthesized, and characterized using modern spectroscopic methods to yield 17 compounds (6a-6q) that were screened for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes in the search for 'lead' compounds for Alzheimer's disease treatment (AD). The compounds 6q, 6p, 6k, 6o, and 6l showed inhibitory capability against AChE and BChE, with IC50 values ranging from 11.73±0.49 to 27.36±0.29 μM for AChE and 21.83±0.39 to 39.43±0.44 μM for BChE, inhibiting both enzymes within a limited range. The SAR ascertained that the substitution of the aromatic moiety had a profound effect on the AChE and BChE inhibitory potential as compared to the aliphatic substitutions which were supported by the molecular docking studies. The drug-likeness of the most synthesized compounds was confirmed by in silico ADME investigations. These results were additionally supplemented by the molecular orbital analysis (HOMO-LUMO) and electrostatic potential maps got from DFT calculations. ESP maps expose that on all structures, there are two potential binding sites conquered by the most positive and most negative districts.

Synthesis and Biological Evaluation of Arylamide Sulphonate Derivatives as Ectonucleotide Pyrophosphatase/Phosphodiesterase-1 and -3 Inhibitors.

Aberrant level of ectonucleotide pyrophosphatase/phosphodiesterase-1 and -3 is linked with numerous disorders, for instance, diabetes, cancer, osteoarthritis, chondrocalcinosis, and allergic reactions. These disorders may be cured or minimized by blocking the activity of ENPP1 and ENPP3 isozymes. In this study, arylamide sulphonates were synthesized, characterized, and evaluated for their capability to affect the activity of isozymes ENPP1 and ENPP3. Among the selective inhibitors of ENPP1, compounds 4f and 4q exhibited sub-micromolar IC50 values of 0.28 ± 0.08 and 0.37 ± 0.03 μM, respectively, followed by 7a, with IC50 equal to 0.81 ± 0.05 μM, whereas out of the selective inhibitors of isozyme ENPP3, 4t and 7d preferably lessened the activity to half of the maximal inhibitory concentration of 0.15 ± 0.04 and 0.16 ± 0.01 μM alternatively. In addition, many structures including 4c, 4g, 4k, 4l, 4n, 4o, 4r, 4s, 7b, 7c, and 7e inhibited the activity of both isozymes to a significant level. Enzyme kinetic study of compound 4j revealed an uncompetitive mode of inhibition of ENPP1 isozyme, while 7e competitively blocked the activity of ENPP3. Cell viability analysis revealed the compound 4o as a cytotoxic agent against MCF7 (human breast cancer cell line) with a percentage inhibition of 63.2 ± 2.51%, whereas compounds 4c, 4d, 4n, and 7d decreased the HeLa cell viability (human cervical cancer cell line) to more than 50%. The tested compounds were non-cytotoxic against HEK293 (a human embryonic kidney cell line). Molecular docking analysis of selected inhibitors of both isozymes produced optimistic interactions with the influential amino acids, such as Leu290, Lys295, Tyr340, Asp376, His380, and Pro323 of ENPP1, whereas residues Asn226, His329, Leu239, Tyr289, Pro272, Tyr320, and Ala205 of ENPP3 crystallographic structure formed interactions with the potent inhibitors.

L-proline catalyzed ring transformation of 5-substituted tetrazole to 1,3,4-oxadiazoles as anti-tubercular agents

An innovative class of novel 2-aryl-5-(1-aryl-1H-pyrazol-3-yl)-1,3,4-oxadiazoles 5i–w have been synthesized from ring transformation using L-proline as an organocatalyst. This novel method using organocatalyst is a splendid example of the green reaction with improved yields. The molecular docking analysis of compounds 5i–w were investigated with enoyl-acyl carrier protein reductase (InhA) enzyme (PDB ID: 4TZK) as anti-tubercular target molecules. The docking study implied that the synthesized compounds exhibited favorable binding modes and affinity. Further, the anti-tubercular activity was investigated against Mycobacterium tuberculosis (MTB) H37Rv strain which demonstrated that the compounds 5i, 5j, 5k, and 5l exhibited excellent activity at the 6.25 µg/ml concentrations, whereas the compounds 5m, 5n, 5o, 5s, and 5w have shown the activity at 12.50 µg/ml concentration, respectively.

Design, synthesis and in vitro antimicrobial activity of fused pyridine-pyrimidine hybrids

The antimicrobial resistance (AMR) is defined as the rising global concern of infectious illnesses that are resistant to all known antimicrobial agents. The discovery of novel antimicrobial agents is required as microbial resistance increases. Due to this reason, we have synthesized a series of novel pyridine-pyrimidine derivatives ( 4a-o ) for the development of antimicrobial agents. The structures of these bioactive molecules were determined using IR, 1 H NMR, 13 C NMR, and mass spectroscopy. The titled compounds were tested for antimicrobial activity against various bacterial and fungal strains using chloramphenicol and griseofulvin as standard drugs. Compounds 4b, 4d and 4m exhibited excellent antibacterial activity with MIC = 62.5 µg/mL against E. coli, S. aureus and S. pyogenes respectively. Compounds 4g and 4o showed prominent activity against C. albicans with MIC value of 250 µg/mL.

Synthesis, molecular docking, anti-cancer activity, and in-silico ADME analysis of novel spiroacenaphthylene pyrrolizidine derivatives

A short and efficient multicomponent sequence for synthesizing spiroacenaphthylene pyrrolizidine analogs 5a-svia 1,3-dipolar cycloaddition reaction of azomethine ylide with chalcones 4a-s without any catalyst. Synthesized compounds 5a-s were characterized by spectral data and single crystal X-ray diffraction study. In-vitro anti-proliferative activity of compounds 5a-s against K562-leukemia showed that compounds 5e, 5i, 5l, 5m and 5o have an IC50 value of 54.07, 47.48, 50.57, 53.85 and 49.57 µg/ml respectively and exhibited H-bonding with LYS 875 in the molecular docking studies against the 2J5F protein and showed favourable in-silico ADME properties. Compound 5o showed favourable in-vitro anti-proliferative activity against K562-leukemic cell line and favourable in-silico ADME properties. It can serve as a template to develop further as a lead molecule and act as a tyrosine kinase inhibitor.

4-Chlorophenyl-N-furfuryl-1,2,4-triazole Methylacetamides as Significant 15-Lipoxygenase Inhibitors: an Efficient Approach for Finding Lead Anti-inflammatory Compounds.

Lipoxygenases (LOXs) are a class of enzymes that catalyze the production of pro-inflammatory mediators, such as leukotrienes and lipoxins, via an arachidonic acid cascade as soon as they are released from the membrane phospholipids after tissue injury. In continuation of our efforts in search for new LOX inhibitors, a series of chlorophenyl-furfuryl-based 1,2,4-triazole derivatives were prepared and evaluated for their 15-LOX inhibitory activities. A simple precursor, 4-chlorobenzoic acid (a), was consecutively transformed into benzoate (1), hydrazide (2), semicarbazide (3), and N-furfuryl 5-(4-chlorobenzyl)-4H-1,2,4-triazole (4), which when further merged with electrophiles (6a–o) resulted in end products (7a–o). The structural elucidations of the newly synthesized compounds (7a–o) were carried out by Fourier transform infrared, 1H-, 13C NMR spectroscopy, EI-MS, and HR-EI-MS spectrometry. The inhibitive capability of compounds (7a–o) on soybean 15-LOX was performed in vitro using the chemiluminescence method. The compounds 7k, 7o, 7m, 7b, and 7i demonstrated potent activities (IC50 17.43 ± 0.38, 19.35 ± 0.71, 23.59 ± 0.68, 26.35 ± 0.62, and 27.53 ± 0.82 μM, respectively). These compounds revealed 79.5 to 98.8% cellular viability as measured by the MTT assay at 0.25 mM concentration. The structure-activity relationship (SAR) studies showed that the positions and the nature of substituents bonded to the phenyl ring are important in the determination of 15-LOX inhibitory activities. ADME, in silico, and density functional theory studies supported the evidence as yet another class of triazoles with potential lead properties in search for anti-LOX compounds with a safe gastrointestinal safety profile for various inflammatory diseases. Further work is in progress on the synthesis of more derivatives in search for anti-inflammatory agents.

Discovery of potent antitubercular agents: Design, synthesis and biological evaluation of 4-(3-(4-substitutedpiperazin-1-yl)-quinoxalin-2-yl)-naphthalen-1-ol analogues

A series of twenty-five novel 4-(3-(4-substituted piperazin-1-yl)-quinoxalin-2-yl)-naphthalen-1-ol analogues were synthesized, characterized and screened for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain. These compounds exhibited minimum inhibitory concentration in the range of 1.56–50 μg/mL. Among these derivatives, compounds 5a, 5b, 5f, 5m, 5p, and 5r displayed moderate activity (MIC 6.25 μg/mL). Compounds 5c, 5d, 5g, 5l, and 5o showed significant antitubercular activity (MIC 3.125 μg/mL), while compounds 5h, 5n, and 5q exhibited potent antitubercular activity (MIC 1.56 μg/mL). In addition, MTT assay was performed on the active analogues of the series against mouse macrophage cells to assess the cytotoxic effect of the newly synthesized compounds, and a selectivity index of the compounds was established. Selectivity index values of the most active compounds (5h, 5n, and 5q) are >47, indicating the compounds' suitability for further potential drug development. A molecular docking study was performed to understand the putative binding mode and binding strength of the selected significantly active and weakly active compounds with the target enzyme mycobacterial topoisomerase II using moxifloxacin as standard. In-silico ADME prediction and bioavailability studies of the titled compounds obey Lipinski's rule of five and Jorgensen's rule of three. To further ascertain the structure of the compounds, a suitable single crystal for the compounds 5a, 6, and 7d was developed and studied.

Explorations of novel pyridine-pyrimidine hybrid phosphonate derivatives as aurora kinase inhibitors

For developing novel therapeutic agents with good anticancer activities, a series of novel pyridine-pyrimidine hybrid phosphonate derivatives4(a–q) were synthesized by the Kabachnik-Fields method using CAN as catalyst. The compound 4o exhibited the most potent anticancer activity with an IC50 value of 13.62 μM, 17.49 μM, 5.81 μM, 1.59 μM and 2.11 μM against selected cancer cell lines A549, Hep-G2, HeLa, MCF-7, and HL-60, respectively. Compound 4o displayed seven times more selectivity towards Hep-G2 cancer cell lines compared to the human normal hepatocyte cell line LO2 (IC50 value 95.33 μM). Structure-Activity Relationship (SAR) studies were conducted on the variation in the aromatic ring (five-membered heterocyclic ring, six-membered heterocyclic ring) and the variation of substituents on the phenyl ring (electron donating groups, electron withdrawing groups). Furthermore, the mechanism of anticancer activity was clarified by further explorations in bioactivity by using in vitro aurora kinase inhibitory activity and molecular docking studies. The results showed that the compound 4o at IC50concentrationdemonstrated distinctive morphological changes such as cell detachment, cell wall deformation, cell shrinkage and reduced number of viable cells in cancer cell lines. Compound 4o induced early apoptosis and late apoptosis of 27.7% and 6.1% respectively.

In vitro antimicrobial combat, molecular modelling and structure activity relationship studies of novel class of aryl-ethyne tethered coumarin analogues and some 3-aryl coumarin derivatives

A series of novel class of aryl ethyne-tethered coumarin analogues (series 1) and some 3-aryl coumarin cognates (series 2) were synthesized, and their in vitro antimicrobial activities aided by molecular modelling and the structure activity relationship (SAR) has been studied. Compounds 1e, 1g, 1h, 1m, 1o and 2e, 2f, 2g, 2h, 2i displayed excellent antimicrobial activities against the screened microbial strains with very good minimum inhibitory concentrations. Perhaps, from the present study, compounds 1g, 1e, 2f and 2h emerge out to be the most promising antimicrobial agents with MICs of 1–4 ​μg/mL. Further, molecular modelling study had also supported these outcomes by demonstrating very good binding affinities at the active site of the protein 1AI9 (Candida albicans dihydrofolate reductase - C. albicans DHFR) up to 6.24 ​kcal/mol and 5.48 ​kcal/mol, close to that of the standard drugs, iterating the possible drug like properties of some of these molecules.