Synthesis of sulfonamide,amide and amine hybrid pharmacophore,an entry of new class of carbonic anhydrase II inhibitors and evaluation of chemo-informatics and binding analysis

Selective inhibition of carbonic anhydrase (CA) enzyme is an active area of research for medicinal chemists. In the current account, a hybrid pharmacophore approach was employed to design sulfonamide, amide and amine containing new series of potent carbonic anhydrase II inhibitors. The aromatic fragment associated with pharmacophore was altered suitably in order to find effective inhibitors of CA-II. All the derivatives 4a-4m showed better inhibition compared to the standard acetazolamide. In particular, compound 4l exhibited significant inhibition with IC₅₀ value of 0.01796 ± 0.00036 µM. The chemo-informatics analysis justified that all the designed compounds possess <10 HBA and <5 HBD. The ligands-protein binding analyses showed that 4l confined in the active binding pocket with three hydrogen bonds observed with His63, Asn66 and Thr197 residues.     

Design,synthesis and molecular modeling study of certain VEGFR-2 inhibitors based on thienopyrimidne scaffold as cancer targeting agents

Different series of novel thieno [2,3-d]pyrimidine derivative (9a-d,10a-f,l,m and 15a-m) were designed, synthesized and evaluated for their ability to in vitro inhibit VEGFR-2 enzyme. Also, the cytotoxicity of the final compounds was tested against a panel of 60 different human cancer cell lines by NCI. The VEGFR-2 enzyme inhibitory results revealed that compounds 10d, 15d and 15 g are among the most active inhibitors with IC₅₀ values of 2.5, 5.48 and 2.27 µM respectively, while compound 10a remarkably showed the highest cell growth inhibition with mean growth inhibition (GI) percent of 31.57%. It exhibited broad spectrum anti-proliferative activity against several NCI cell lines specifically on human breast cancer (T7-47D) and renal cancer (A498) cell lines of 85.5% and 77.65% inhibition respectively. To investigate the mechanistic aspects underlying the activity, further biological studies like flow cytometry cell cycle together with caspase-3 colorimetric assays were carried on compound 10a. Flow cytometric analysis on both MCV-7 and PC-3 cancer cells revealed that it induced cell-cycle arrest in the G0-G1phase and reinforced apoptosis via activation of caspase-3. Furthermore, molecular modeling studies have been carried out to gain further understanding of the binding mode in the active site of VEGFR-2 enzyme and predict pharmacokinetic properties of all the synthesized inhibitors.     

Novel [1,2,4]triazolo[1,5-a]pyrimidine derivatives as potent antitubulin agents: Design,multicomponent synthesis and antiproliferative activities

As restricted CA-4 analogues, a novel series of [1,2,4]triazolo[1,5-a]pyrimidines possessing 3,4,5-trimethoxylphenyl groups has been achieved successfully via an efficient one-pot three-component reaction of 3-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazol-5-amine, 1,3-dicarbonyl compounds and aldehydes. Initial biological evaluation demonstrated some of target compounds displayed potent antitumor activity in vitro against three cancer cell lines. Among them, the most highly active analogue 26 inhibited the growth of HeLa, and A549 cell lines with IC₅₀ values at 0.75, and 1.02 μM, respectively, indicating excellent selectivity over non-tumoural cell line HEK-293 (IC₅₀ = 29.94 μM) which suggested that the target compounds might possess a high safety index. Moreover, cell cycle analysis illustrated that the analogue 26 significantly induced HeLa cells arrest in G2/M phase, meanwhile the compound could dramatically affect cell morphology and microtubule networks. In addition, compound 28 exhibited potent anti-tubulin activity with IC₅₀ values of 9.90 μM, and molecular docking studies revealed the analogue occupied the colchicine-binding site of tubulin. These observations suggest that [1,2,4]triazolo[1,5-a]pyrimidines represent a new class of tubulin polymerization inhibitors and well worth further investigation aiming to generate potential anticancer agents.     

Synthesis and evaluation of 2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione derivatives as Mnk inhibitors

Post-translational modulation of eIF4E through phosphorylation by Mnks is highly integral to the pathogenesis of different cancers. Therefore, inhibition of Mnks offers a strategy for cancer treatment. Herein, a series of 2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione derivatives is presented as Mnk inhibitors. Some of them showed sub-micromolar to low nanomolar inhibitory activities against Mnk1/2 with a high level of selectivity for both kinases over CDKs. Biochemical assays revealed that compounds 4c and 4t are non-ATP-competitive inhibitors of Mnks. Lead compound 4t demonstrated a high selectivity for Mnk1/2 over a selection of 51 kinases, and displayed anti-proliferative activities against a panel of cancer cell lines. However, this compound in combination with our in-house CDK4/6 inhibitor 83 did not show a synergistic effect in A2780 ovarian cancer cells, suggesting that caution be exercised in the selection of an agent to be combined with an Mnk inhibitor.     

Pyrazolopyrimide library screening in glioma cells discovers highly potent antiproliferative leads that target the PI3K/mTOR pathway

The search for novel targeted inhibitors active on glioblastoma multiforme is crucial to develop new treatments for this unmet clinical need. Herein, we report the results from a screening campaign against glioma cell lines using a proprietary library of 100 structurally-related pyrazolopyrimidines. Data analysis identified a family of compounds featuring a 2-amino-1,3-benzoxazole moiety (eCF309 to eCF334) for their antiproliferative properties in the nM range. These results were validated in patient-derived glioma cells. Available kinase inhibition profile pointed to blockade of the PI3K/mTOR pathway as being responsible for the potent activity of the hits. Combination studies demonstrated synergistic activity by inhibiting both PI3Ks and mTOR with selective inhibitors. Based on the structure activity relationships identified in this study, five new derivatives were synthesized and tested, which exhibited potent activity against glioma cells but not superior to the dual PI3K/mTOR inhibitor and lead compound of the screening eCF324.     

5-Arylidene-2-phenylimino-4-thiazolidinones as PTP1B and LMW-PTP inhibitors

As part of a project aimed at identifying effective low molecular weight nonphosphorus monoanionic inhibitors of PTPs, we have synthesized 4-[(5-arylidene-4-oxo-2-phenyliminothiazolidin-3-yl)methyl]benzoic acids (4) and evaluated their inhibitory activity against human PTP1B and LMW-PTP enzymes. The introduction of a 2-phenylimino moiety onto the 4-thiazolidinone ring was designed to enhance the inhibitor/enzyme affinity by means of further favourable interactions with residues of the active site and the surrounding loops. Some of the compounds (4a–d, f) showed interesting inhibition levels in the low micromolar range. The 5-arylidene moiety of acids 4 proved to markedly influence the potency of these inhibitors. Molecular modeling experiments inside the binding sites of both enzymes were performed.     

New pyrazoline bearing 4(3H)-quinazolinone inhibitors of monoamine oxidase: Synthesis,biological evaluation,and structural determinants of MAO-A and MAO-B selectivity

A new series of pyrazoline derivatives were prepared starting from a quinazolinone ring and evaluated for antidepressant, anxiogenic and MAO-A and -B inhibitory activities by in vivo and in vitro tests, respectively. Most of the synthesized compounds showed high activity against both the MAO-A (compounds 4a–4h, 4j–4n, and 5g–5l) and the MAO-B (compounds 4i and 5a–5f) isoforms. However, none of the novel compounds showed antidepressant activity except for 4b. The reason for such biological properties was investigated by computational methods using recently published crystallographic models of MAO-A and MAO-B. The differences in the intermolecular hydrophobic and H-bonding of ligands to the active site of each MAO isoform were correlated to their biological data. Compounds 4i, 4k, 5e, 5i, and 5l were chosen for their ability to reversibly inhibit MAO-B and MAO-A and the availability of experimental inhibition data. Observation of the docked positions of these ligands revealed interactions with many residues previously reported to have an effect on the inhibition of the enzyme. Among the pyrazoline derivatives, it appears that the binding interactions for this class of compounds are mostly hydrophobic. All have potential edge-to-face hydrophobic interactions with F343, as well as π–π stacking with Y398 and other hydrophobic interactions with L171. Strong hydrophobic and H-bonding interactions in the MAO recognition of 4i could be the reason why this compound shows selectivity toward the MAO-B isoform. The very high MAO-B selectivity for 4i can be also explained in terms of the distance between the FAD and the compound, which was greater in the complex of MAO-A-4i as compared to the corresponding MAO-B complex.     

New benzoxanthone derivatives as topoisomerase inhibitors and DNA cross-linkers

We synthesized 12 benzoxanthone derivatives classified as three different groups based on the tetracyclic ring shapes and evaluated their pharmacological activities to find potential anticancer agents. In the cytotoxicity test, most compounds showed effective cancer cell growth inhibition against the HT29 and DU145 cell lines. Among the compounds tested, compound 19 was the most effective in the cancer cell lines tested. Compound 9 showed dual inhibitory activities against DNA relaxation by topoisomerases I and II. The% inhibition of compound 9 on topoisomerase I was comparable to that of camptothecin. Compound 9 efficiently blocked topoisomerase II function by almost threefold than etoposide at 20 μM. Compound 19 had selective topoisomerase II inhibitory activity at 100 μM. The DNA cross-linking test revealed that only compounds 8 and 19, which possess epoxy groups, cross-linked DNA duplex, while 14 did not. From the combined pharmacological results, we proposed that the target through which compound 19 inhibits cancer cell growth may be the DNA duplex itself and/or DNA–topoisomerase II complex.     

Synthesis and biological evaluation of novel carbazole-rhodanine conjugates as topoisomerase II inhibitors

In this study, a series of carbazole-rhodanine conjugates was synthesized and evaluated for their Topoisomerase II inhibition potency as well as cytotoxicity against a panel of four human cancer cell lines. Among these thirteen compounds, 3a, 3b, 3g, and 3h possessed Topoisomerase II inhibition potency at 20?μM. Mechanism study revealed that these compounds may function as Topo II catalytic inhibitors. It was found that the electron-withdrawing groups on the phenyl ring of compounds played an important role on enhancing both enzyme inhibition and cytotoxicity.     

Synthesis,selective cytotoxicities and probable mechanism of action of 7-methoxy-3-arylflavone-8-acetic acids

Thirteen new analogues of flavone-8-acetic acid, that is, compounds 10a–m bearing a methoxy group at the 7-position and diverse subsitiuents on the benzene ring at the 2- and 3-positions of flavone nucleus, were synthesized and evaluated for their direct antiproliferative effects on two human tumor cell lines and for their indirect antiproliferative activities in the transwell co-culture system. The results indicated that most of compounds 10a–m showed moderate direct cytotoxicities. Among them, compound 10i exhibited higher direct cytotoxicity and selectivity for both cell lines over BJ human foreskin fibroblast cells than 5,6-dimethylxanthenone-4-acetic acid (DMXAA). Interestingly, compared with DMXAA, compound 10e showed comparable indirect cytotoxicity and higher selectivity. In addition, compound 10e was found to be able to induce tumor necrosis factor α (TNF-α) production in human peripheral blood mononuclear cells.     

Design,synthesis and biological evaluation of lazabemide derivatives as inhibitors of monoamine oxidase

In the studied a series novel of lazabemide derivatives were designed, synthesized and evaluated as inhibitors of monoamine oxidase (MAO-A or MAO-B). These compounds used lazabemide as the lead compound, and the chemistry structures were modified by used the bioisostere and modification of compound with alkyl principle. The two types of inhibitors (inhibition of MAO-A and inhibition of MAO-B) were screened by inhibition activity of MAO. In vitro experiments showed that compounds 3a, 3d and 3f had intensity inhibition the biological activity of MAO-A, while compounds 3i and 3m had intensity inhibition the biological activity of MAO-B. It could be seen from the data of inhibition activity experiments in vitro, that the compound 3d was IC₅₀?=?3.12?±?0.05?μmol/mL of MAO-A and compound 3m was IC₅₀?=?5.04?±?0.06?μmol/mL. In vivo inhibition activity experiments were conducted to evaluate the inhibitory activity of compounds 3a, 3d, 3f, 3i and 3m by detecting the contents of 5-HT, NE, DA and activity of MAO-A and MAO-B in plasma and brain tissue. In vivo inhibition activity evaluation results showed that the compounds 3a, 3d, 3f, 3i and 3m had increased the contents of 5-HT, NE and DA in plasma and brain tissues. Meanwhile, the determination results activity of MAO in plasma and brain tissue showed that the compounds 3a, 3d, and 3f had a significant inhibitory effect on the activity of MAO-A, while the compounds 3i and 3m showed inhibitory effect on the activity of MAO-B. This study provided a new inhibitors for inhibiting of MAO activity.     

Synthesis of indazole based diarylurea derivatives and their antiproliferative activity against tumor cell lines

New series of indazole based diarylureas were synthesized and their anticancer activity against cancer cells H460, A549, OS-RC-2, HT-29, Lovo, HepG2, Bel-7402, SGC-7901 and MDA-MB-231 were examined. These derivatives of diarylureas, except azaindazole based diarylureas 5f, 5l and 5m, showed superior or similar activity against most of these selected cancer cell lines to the reference compound sorafenib. The effect of substituents on the indazole ring was also investigated. Derivatives with trifluoromenthy or halogen substituent on the indazole ring showed higher activity against the selected cancer cell lines than sorafenib. The acute toxicity assay showed that compounds 5a, 5b and 5i possessed lower toxicity than sorafenib. Compound 5i with 4-(trifluoromenthy)-1H-indazole and 4-(trifluoromenthy) benzene moieties exhibited the most potent anticancer activity.     

Synthesis and biological evaluation of some novel thiobenzimidazole derivatives as anti-renal cancer agents through inhibition of c-MET kinase

Benzimidazole is an interesting scaffold constituting a main core in many anticancer agents against variable cell lines as Carbendazim (I) and Nocodazole (II). Accordingly, eighteen compounds of 2-((1H-benzoimidazol-2-yl)thio)-1-(aryl/heteroaryl)ethan-1-ones, in their sulfate salt and free forms, were designed and investigated as anticancer agents. In vitro preliminary screening of selected compounds by the National Cancer Institute (NCI) on a panel of 60 cell lines revealed renal cancer cell line (A498) as the most vulnerable cell line; accordingly, IC₅₀ values against A498 cell line were determined for compounds with the best results. The best inhibitory activity was for compound 4a with (IC₅₀ = 6.97 µM) compared to sunitinib as a reference drug (IC₅₀ = 6.99 µM). Compound 4a was further subjected to cell cycle analysis that indicated the decrease in cell population in the G2/M phase when compared to the untreated control cells. In addition, it showed significant increase in the late apoptosis in Annexin-V FTIC study compared to the control cells. An enzymatic inhibitory study on compound 4a against c-Met and MAP kinases revealed its better activity against c-Met kinase with (IC₅₀ = 0.27 µM) compared to sunitinib (IC₅₀ = 0.18 µM). Molecular docking study was conducted to reveal the interactions of compound 4a in the active site of c-Met kinase. Computational ADME study was performed to insure that compound 4a has proper pharmacokinetic and drug-likeness properties.     

Benzene-1,3-dicarboxylic acid 2,5-dimethylpyrrole derivatives as multiple inhibitors of bacterial Mur ligases (MurC–MurF)

Enzymes catalyzing the biosynthesis of bacterial peptidoglycan represent traditionally a collection of highly selective targets for novel antibacterial drug design. Four members of the bacterial Mur ligase family—MurC, MurD, MurE and MurF—are involved in the intracellular steps of peptidoglycan biosynthesis, catalyzing the synthesis of the peptide moiety of the Park’s nucleotide. In our previous virtual screening campaign, a chemical class of benzene-1,3-dicarboxylic acid 2,5-dimethylpyrrole derivatives exhibiting dual MurD/MurE inhibition properties was discovered. In the present study we further investigated this class of compounds by performing inhibition assays on all four Mur ligases (MurC–MurF). Furthermore, molecular dynamics (MD) simulation studies of one of the initially discovered compound 1 were performed to explore its geometry as well as its energetic behavior based on the Linear Interaction Energy (LIE) method. Further in silico virtual screening (VS) experiments based on the parent active compound 1 were conducted to optimize the discovered series. Selected hits were assayed against all Escherichia coli MurC–MurF enzymes in biochemical inhibition assays and molecules 10–14 containing benzene-1,3-dicarboxylic acid 2,5-dimethylpyrrole coupled with five member-ring rhodanine moiety were found to be multiple inhibitors of the whole MurC–MurF cascade of bacterial enzymes in the micromolar range. Steady-state kinetics studies suggested this class to act as competitive inhibitors of the MurD enzyme towards d-Glu. These compounds represent novel valuable starting point in the development of novel antibacterial agents.     

Synthesis of 3-acyloxyxanthone derivatives as α-glucosidase inhibitors: A further insight into the 3-substituents’ effect

Considerable interest has been attracted in xanthone and its derivatives because of their important biological activities. In this paper, a series of novel 3-arylacyloxyxanthone derivatives 2a–p were synthesized and evaluated for their biological activities toward α-glucosidase. In comparison to the parent 1,3-dihydroxylxanthone 1a, 3-arylacyloxy derivatives 2a–p with additional aromatic ester groups at 3-position show up to 13.7-fold higher inhibitory activities. In particular, the IC₅₀ values of compounds 2i, 2m, 2p reach 13.3, 10.6, 11.6 μM, respectively. These results suggest that addition of aromatic moieties by esterification at the 3-OH of the parent 1,3-dihydroxylxanthone is an efficient way to increase the inhibition against α-glucosidase. Different from previous multi-hydroxylxanthones, these 3-arylacyloxyxanthone derivatives show efficient inhibitory activities may due to the π-stacking or hydrophobic effects of the additional aromatic moieties rather than the H-bonding donor interaction of 3-OH. Structure–activity relationship analysis shows that the substituents on the additional aromatic ring also influence the inhibition. All the oxygen or nitrogen-containing groups, like hydroxyl, methoxy, methaminyl, and alkylsilyloxy, can enhance the inhibitory activities. In addition, the kinetics of enzyme inhibition measured by using Lineweaver–Burk plots shows that selected compounds 2i, 2m and 2p are non-competitive inhibitors. Docking simulations further support our structure–activity relationship analysis that additional aromatic moieties enhance inhibitory activities via hydrophobic effects. The new developed 3-arylacyloxyxanthone derivatives probably bind with α-glucosidase in an allosteric site different from traditional multi-hydroxylxanthones.     

Design,synthesis and biological research of novel N-phenylbenzamide-4-methylamine acridine derivatives as potential topoisomerase I/II and apoptosis-inducing agents

A series of novel N-phenylbenzamide-4-methylamine acridine derivatives were designed and synthesized based initially on the structure of amsacrine (m-AMSA). Molecular docking suggested that the representative compound 9a had affinity for binding DNA topoisomerase (Topo) II, which was comparable with that of m-AMSA, and furthermore that 9a could have preferential interactions with Topo I. After synthesis of 9a and analogues 9b-9f, these were all tested in vitro and the synthesized compounds displayed potent antiproliferative activity against three different cancer cell lines (K562, CCRF-CEM and U937). Among them, compounds 9b, 9c and 9d exhibiting the highest activity with IC₅₀ value ranging from 0.82 to 0.91 μM against CCRF-CEM cells. In addition, 9b and 9d also showed high antiproliferative activity against U937 cells, with IC₅₀ values of 0.33 and 0.23 μM, respectively. The pharmacological mechanistic studies of these compounds were evaluated by Topo I/II inhibition, western blot assay and cell apoptosis detection. In summary, 9b effectively inhibited the activity of Topo I/II and induced DNA damage in CCRF-CEM cells and, moreover, significantly induced cell apoptosis in a concentration-dependent manner. These observations provide new information and guidance for the structural optimization of more novel acridine derivatives.     

Novel 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives as potent phosphoinositide 3-kinase delta (PI3Kδ) inhibitors

In this study, a novel series of 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives were designed and evaluated as potent PI3Kδ inhibitors. The preliminary SAR was established, and compounds 12d, 20a and 20c displayed leading potent PI3Kδ inhibition, with IC₅₀ values of 4.5, 2.7 and 3.1?nM, respectively, that were comparable to idelalisib (IC₅₀?=?2.7?nM). Moreover, these three compounds showed favorable PI3Kδ isoform selectivity over PI3Kα, PI3Kβ, and PI3Kγ, and showed distinct anti-proliferation profiles against four human B cell lines of Ramos, Raji, RPMI-8226 and SU-DHL-6. In addition, molecular docking simulation showed that several key hydrogen bonding interactions were formed for compounds 12d, 20a and 20c in the PI3Kδ pocket, which might explain their potent PI3Kδ inhibition. These results indicate the 6-aryl substituted 4-pyrrolidineaminoquinazolines were potent PI3Kδ inhibitors.     

In vitro and in silico evaluation of new thiazole compounds as monoamine oxidase inhibitors

New twenty compounds bearing thiazole ring (3a-3t) were designed and synthesized as monoamine oxidase (MAO) inhibitors. The fluorometric enzyme inhibition assay was used to determine the biological effects of synthesized compounds. Most of them showed remarkable inhibitory activity against both MAO-A and MAO-B. By comparing their IC₅₀ values, it can be seen that active derivatives displayed generally selectivity on MAO-B enzyme. Compounds 3j and 3t, which bear dihydroxy moiety at the 3rd and 4th position of phenyl ring, were the most active derivatives in the series against both isoenzymes. Compounds 3j and 3t showed significant inhibition profile on MAO-A with the IC₅₀ values of 0.134 ± 0.004 µM and 0.123 ± 0.005 µM, respectively, while they performed selectivity against MAO-B with the IC₅₀ values of 0.027 ± 0.001 µM and 0.025 ± 0.001 µM, respectively. Also, docking studies about these compounds were carried out to evaluate their binding modes on the active regions of MAO-A and MAO-B.     

New amide linked dimeric 1,2,3-triazoles bearing aryloxy scaffolds as a potent antiproliferative agents and EGFR tyrosine kinase phosphorylation inhibitors

A search for potent antiproliferative agents has prompted to design and synthesize aryloxy bridged and amide linked dimeric 1,2,3-triazoles (7a–j) by using 1,3-dipolar cycloaddition reaction between 2-azido-N-phenylacetamides (4a–e) and bis(prop-2-yn-1-yloxy)benzenes (6a–b) via copper (I)-catalyzed click chemistry approach with good to excellent yields. All the newly synthesized compounds have been screened for their in vitro antiproliferative activities against two human cancer cell lines. The compounds 7d, 7e, 7h, 7i and 7j have revealed promising antiproliferative activity against human breast cancer cell line (MCF-7), whereas, the compounds 7a, 7b, 7c, 7i and 7j were observed as potent antiproliferative agents against human lung cancer cell line (A-549). The active compounds against MCF-7 have been also analysed for their mechanism of action by the enzymatic study, which shows that the compounds 7d, 7h and 7j were acts as active EGFR tyrosine kinase phosphorylation inhibitors. In support to this biological study, the molecular docking as well as in silico ADME properties of all the newly synthesized hybrids were predicted.     

Probing the high potency of pyrazolyl pyrimidinetriones and thioxopyrimidinediones as selective and efficient non-nucleotide inhibitors of recombinant human ectonucleotidases

With the aim to discover novel, efficient and selective inhibitors of human alkaline phosphatase and nucleotide pyrophosphatase enzymes, two new series of pyrazolyl pyrimidinetriones (PPTs) (6a–g) and thioxopyrimidinediones (PTPs) (6h–n) were synthesized in good chemical yields using Knoevenagel condensation reaction between pyrazole carbaldehydes (4a–g) and pharmacologically active N-alkylated pyrimidinetrione (5a) and thioxopyrimidinedione (5b). The inhibition potential of the synthesized hybrid compounds was evaluated against human alkaline phosphatase (h-TNAP and h-IAP) and ectonucleotidase (h-NPP1 and h-NPP3) enzymes. Most of the tested analogs were highly potent with a variable degree of inhibition depending on the functionalized hybrid structure. The detailed structure-activity relationship (SAR) of PPT and PTP derivatives suggested that the compound with unsubstituted phenyl ring from PPT series led to selective and potent inhibition (6a; IC₅₀ = 0.33 ± 0.02 µM) of h-TNAP, whereas compound 6c selectively inhibited h-IAP isozyme with IC₅₀ value of 0.86 ± 0.04 µM. Similarly, compounds 6b and 6h were identified as the lead scaffolds against h-NPP1 and h-NPP3, respectively. The probable binding modes for the most potent inhibitors were elucidated through molecular docking analysis. Structure-activity relationships, mechanism of action, cytotoxic effects and druglikeness properties are also discussed.