Letters in Drug Design & Discovery - Volume 15, Issue 1, 2018

Background: Mycothiol (MSH), a thiol compound found in Mycobacterium tuberculosis is required for the growth and survival of bacteria. This unusual compound is found only in actinomycetes. MSH biosynthesis involves many enzymes, one of them is MshC an essential enzyme for M. tuberculosis. Methods: NTF1836 were the first MSH biosynthesis inhibitors identified. QSAR studies were performed on a novel series of NTF1836 as an inhibitor of MshC (enzyme involved in the synthesis of mycothiol). The series of molecules were subjected to CoMFA, CoMSIA and HQSAR studies. Results: The resulted model exhibited good correlation coefficient (r2) of 0.98, 0.87, 0.81 and cross validated correlation coefficient (q2) of 0.76, 0.60, and 0.61 for CoMFA, CoMSIA and HQSAR methods respectively. Contour map analysis revealed the importance of steric, electrostatic, donor, acceptor and hydrophobic fields in determining the activity. Conclusion: The results of our structure activity relationships study reveals key contribution and can serve as a basis for future drug development of antitubercular agent.

Background: A series of purinoxyphenoxypropionates were designed and synthesized by introducing 8-(trifluoromethyl)-9H-purine into the aryloxyphenoxypropionate backbone. Methods: The products were characterized by 1H NMR and HRMS. Results and Conclusion: Preliminary bioassays indicated that most of the compounds exhibited good herbicidal activity at 200 mg/L.

Introduction: The escalating threat due to dwindling effect of antibiotics and challenge of tackling rising drug-resistant infections has gathered high focus in current medicinal research. Methods: In an attempt to find new molecules that can defeat microbial resistance, two new series of 2-[2-substituted ethenyl]-5-(substituted methoxy)-1,3,4-oxadiazole derivatives were synthesized. Various aromatic hydrazides were allowed to undergo cyclization to substituted oxadiazole-2- amines in the presence of cyanogen bromide and further condensed with different heterocyclic aldehydes to give new oxadiazole derivatives. The synthesized molecules were fully characterized by various spectral techniques and tested for antimicrobial activity. Results: Almost all the newly synthesized compounds especially (5g-5l) displayed remarkable growth inhibition against three bacterial strains: M. smegmatis, S. aureus, E. coli and fungi C. albicans. The antimicrobial activity was further confirmed by MIC assay against the same microorganisms. Oxadiazole 5g displayed promising activity with a MIC value of 0.025 mM for two bacteria and fungi, whereas MIC of this compound for E. coli was 0.1 mM. Other active compounds (5h-5l) also exhibited good MIC ranging between 0.313 to 5.0 mM against the selected microorganisms. Docking simulations were generated to explore the potential binding approaches of ligand 5g at the D-alanine:d-alanine ligase (Ddl) protein of E. coli and S. aureus. Conclusion: Molecule 5g was active even at a lower concentration and could probably act as a prospective lead molecule for targeting the drug resistant microorganisms.

Background: Chlamydiae, characterized by a unique biphasic life cycle, are a group of Gram-negative obligate intracellular bacterial pathogens responsible for diseases in a range of hosts including humans. Benzylidene acylhydrazide CF0001 could inhibit chlamydiae independent of iron starvation and T3SS inhibition. This finding promoted us to design and synthesize more benzylidene acylhydrazides to find novel anti-chlamydial agents. Methods: The carboxylic acids 1a-1d were coupled with Boc-hydrazide inpresence of EDCI and DMAP to obtain the intermediate 2a-2d in 60-62% yields. N-Boc deprotections were performed to obtain hydrazide hydrochloride salt 3a-3d. Nextly, the hydrazides were subjected to condensation with aldehydes to obtain benzylidene acylhydrazides 4a-4g in 30-52% yields in two steps. Results: Compound 4d exhibited best inhibitory effect on the formation and growth of chlamydial inclusions. The IC50 value of compound 4d for infectious progenies was 3.55 μM, better than 7.30 μM of CF0001. Conclusion: To find novel anti-chlamydial agents, we have designed and synthesized benzylidene acylhydrazides 4a-4g. Compounds 4a, 4d, 4g showed inhibitory activity on C. muridarum with the IC50 values from 3.55-12 μM. The 3,5-dibromo-4-hydroxyl substitutes on ring B are critical to keep their anti-chlamydial activity. Compound 4d inhibited C. muridarum in a dose-dependent manner without apparent cytotoxicity.

Background: Spiro[pyrrolidine-3,3'-oxindole] compounds are reported to be highly bioactive natural and synthetic products. Initially, spirooxindole alkaloids were isolated from plants of the Apocynaceae and Rubiaceae families, which were found to have a common scaffold, spiro[pyrrolidine-3,3'-oxindole], exhibiting anticancer activities., we specifically aimed at the synthesis, characterization and anticancer activity of novel spiro[pyrrolidine-3,3' -oxindole] derivatives, compounds 6a-c and 7. Methods: The synthesis was initiated by Knovenegal condensation of indole-2-one with an appropriate benzaldehyde in presence of piperidine to afford compounds 3a-c. Compounds 6a-c were synthesized by an asymmetric 1,3-dipolar cycloaddition between compounds 3a-c and (2S, 3R)-2, 3, 5, 6-tetrahydro-2, 3-diphenyl-1, 4-oxazin-6-one, which is an intermediate compound formed by the Schiff base reaction between 3-methyl-butanal and (2S, 3R)-2, 3, 5, 6-tetrahydro-2, 3-diphenyl- 1,4-oxazin-6-one, in presence of molecular sieves (4Å) under argon atmosphere. Compound 6a was then reacted with ethylamine-HCl in THF at room temperature to yield compound 7. Results: Cytotoxic effects of the compounds synthesized were determined on Huh7, MV, HCT116 and MCF7 cancer cell lines by the NCI-60 Sulforhodamine B Assay, using (S)-(+)-Camptothecin as a positive control. In general, target compounds showed better cytotoxic activities against the MCF7 and HCT116 cancer cell lines. It was found that compound 7 exhibited the most potent inhibitory activity with IC50 values of 4.8 μM, 3.9 μM, 14.9 μM and 8.2 μM against the MCF7, HCT116, MV and Huh7 cell lines, respectively. Conclusion: It was determined that compounds 6a&6b possess C6'(S)|C8'(R)|C9'(R) stereochemistry and compound 7 adopts C2'(S)|C4'(R)|C5'(R) stereochemistry. Cytotoxicity studies suggest that compound 7 gave rise to the highest anticancer activity against MCF7, HCT116, and Huh7 cancer cell lines.

Background: The synthesis of new hybrid molecules consisting of several heterocyclic pharmacophores namely fluoroquinolone, 1,2,4-triazole, 1,3,4-oxadiazole and piperazine was carried out by conventional and successfully optimized microwave mediated techniques. Methods: The structures of new compounds were confirmed using spectroscopic techniques. These compounds were screened for their antibacterial activity against E. coli, P. aeruginosa, Y. pseudotuberculosis, S. aureus, E. faecalis, B. cereus and M. smegmatis. Results and Conclusion: Fourteen of these hybrids exhibited excellent antibacterial activities on the test microorganisms when compared with ampicillin with the mic values varying between 0.03- 0.25 μg/mL.

Background: Platinum complexes as antitumor agents have received considerable attention due to the clinically approved and have been marketed worldwide such as cisplatin, carboplatin, oxaliplatin or marketed locally such as nedaplatin, lobaplatin and heptaplatin for treatment of various tumor diseases. However, those drugs still had their own defects and they exhibited side effects including nephrotoxicity, ototoxicity, neurotoxicity and bone marrow suppression. Therefore there is still continuing interest in the development of new platinum drugs avoiding their inherent resistance and toxicity. Methods: Two hexa- and tetrachloroplatinate salts and one platinum(II) complex were synthesized and evaluated for their in vitro cytotoxicities against human HeLa, MCF-7, and MDA-MB-231 cell lines by the MTT assay. Results: The growth inhibitory effect values of compounds 1-3, and cisplatin against the cell lines were expressed as inhibition %. Conclusion: Compound 3 showed appreciable activity for all examined cell lines compared to that of reference compound cisplatin.

Background: As reported EGFR is a sialoglycoprotein with tyrosine kinase activity involved in control of cellular survival, multiplication, differentiation and metastasis. Dysregulation or aberrant expression of EGFR has been implicated in cell transformation and having oncogenic roles in a number of human cancers. Therefore EGFR has become a significant target for developing targeted therapy for cancer. Methods: A novel series of indole-3-carboxamide derivatives as EGFR inhibitors were designed, synthesized and evaluated for the anticancer activity in vitro against three EGFR high-expressed cancer cell lines (A549, HeLa, and SW480), one EGFR low-expressed cell line (HepG2) and one human liver normal cell line (HL7702) by MTT assay. Results: The target compounds 6c, 6f, 6i, 6j, 6l, 6r, 6u and 6x exhibited potent anticancer activities against the three tested cancer cell lines and weak cytotoxic effects on HepG2, which imply that the target compounds are probably effective in inhibiting EGFR. And they also did not show measurable activities in HL7702, which imply the target compounds are likely to overcome the nonspecific toxicity against normal cells. Particularly, the target compound 6x indicated equal to the positive control erlotinib. In addition, molecular docking studies demonstrated the target compound 6x may be the potential inhibitor to EGFR. Conclusion: A new EGFR inhibitor scaffold and a preliminary discussion on their SARs provide promising opportunities to guide further research on indole-3-carboxamide derivatives as novel anticancer agents.

Background: Nerium oleander extract preparations have been used in the Arab folkmedicine for the treatment of solid tumors. Objective: In the current investigation, bioassay-guided fractionation of N. oleander stem methanolic extract was performed to identify the active compound(s) responsible for its antiproliferative activity and the mechanism of action of the active compounds was explored. Methods: The methanolic extract, fractions and sub-fractions were screened against four human cancer cell lines: HT-144, MCF-7, NCI-H460 and SF-268 using sulforhodamine B assay. The effects of the active compounds on the cytoskeleton and nuclei of NCI-H460 cells were studied using immunofluorescence microscopy. Results: The more active petroleum ether insoluble sub-fraction led to the isolation of five pure compounds viz adynergenin, adynerin, hemidesmin-2, odoroside A and odoroside B. Odoroside A was the most potent compound with GI50: 0.04 and LC50: 0.74 μM against NCI-H460 cell line, while odoroside B demonstrated moderate growth inhibition and cytotoxicity (GI50: 6.7; LC50: 54 μM). After 24 hours' treatment with odoroside B (50 μM) abnormal mitotic spindles were observed, while > 90% mitotic cells were arrested in the prophase stage. Conclusion: N. oleander stem possesses significant antiproliferative effects against the aforementioned cell lines and the cardenolide odoroside B induces mitotic arrest of NCI-H460 cells in the prophase stage.

Background: Overexpression of Angiotensin Type 1 (AT1) receptor along with other deregulated oncogenic factors, for e.g. Vascular Endothelial Growth Factor (VEGF) triggers angiogenesis, which is one of the hallmarks of cancer. AT1 receptor, being a key component of the renin - angiotensin system (RAS), also helps in the regulation of blood pressure. In the present study, we report on the identification of novel Angiotensin II Type 1 receptor modulators from among the 265,242 molecules deposited in the NCI compound database (Release 4, 2012) by several rounds of In silico screening steps. Methods: The screening steps involved Lipinski's filter to eliminate the non-drug like candidates followed by fingerprint based similarity filtering using 950 known reference set of AT1 receptor binders. Further screening exercises such as, iterative GOLD based docking and binding free energy calculations were performed to arrive at potential AT1 receptor binding hit candidates. The 2D structural and bioactivity data of the known AT1 receptor modulators retrieved from BindingDB database were also critically reviewed. Results: Docking based virtual screening followed by high flexible docking resulted 10 best fit candidates, which had binding modes roughly similar to the cocrystallized ligand, ZD7155. Of the ten shortlisted candidates, NSC407757 had the binding affinity, on-par, as of the known reference ligand, ZD7155 towards AT1 receptor. An interesting observation of this study is that, the high binding affinity of the hit candidates may be attributed to the similar binding orientation and interactions as of the reference molecule independent of structural similarity with the known AT1 receptor modulators. Conclusion: The hit candidates reported in the present study hold promise as the potential new AT1 receptor modulators. Further study involving structural optimization, synthesis and In vitro binding experiments is warranted for the accelerated discovery of high efficacy novel AT1 receptor modulators.

Background: The prevalence of morbidity and mortality due to infections from parasitic worms and protozoa is on rise especially in third world countries. The situation is further worsened by drug resistant microbial pathogens. Objectives: The antimicrobial and anthelmintic activities associated with substituted furfuraldehyde and 1,8-naphthyridine nucleus of nalidixic acid prompted us to synthesize some new quinolone Schiff bases with an aim to obtain potent antibacterial and anthelmintic agents with improved safety and efficacy. Methods: A new series of 1,8 naphthyridine based Schiff bases were designed and synthesized by the reaction of Nalidixic acid methyl ester 1 with hydrazine hydrate in anhydrous condition which yielded 1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carbohydrazide 2. The compound 2 was further treated with several furfural aldehydes to furnish the desired Schiff bases (3a-k). The in vitro antibacterial activity of Schiff bases was investigated against four Gram positive and four Gram negative bacterial strains. The newly prepared Schiff bases were also tested for their anthelmintic activity against Pheritima posthuma and Perionyx excavatus. Results: Chemical structures and identity of the prepared compounds were confirmed by their spectral data. Overall, Schiff bases (3a-k) showed good antimicrobial activity and interestingly five compounds exhibited more potent inhibitory effect than the standard drug Ampicillin against S. aureus, B. cereus, E. faecalis, S. epidermidis, E. coli, S. typhi and S. dysenteriae. Schiff bases also exhibited significant anthelmintic activity as indicated by their mean paralyses time (min) of 7.07-16.49, and 11.23- 20.46 min against Perionyx excavatus and Pheritima posthuma in comparison to the 8.23 and 12.58 min shown by standard drug- Albendazole. Conclusion: It could be proposed that substitution of aromatic ring at C-5 of furfuryl heterocyclic ring in the Schiff bases produce compounds with promising antibacterial and anthelmintic actions.