Synthesis and evaluation of 1,3,5-triazine derivatives as sunscreens useful to prevent skin cancer

The incidence of skin cancers such as non-melanoma skin cancer and malignant melanoma has increased in the last few years mainly because of chronic exposure to ultraviolet (UV) radiation. Sunscreens protect the skin against harmful UV radiations; however, some limitations of these products justify the discovery of new UV filters. Novel 1,3,5-triazine derivatives (12a-h) obtained by the optimization of prototype resveratrol were synthesized and characterized. All compounds exhibited sun protection factor (SPF) and UVA protection factor (UVAPF) in the range of 3–17 and 3–13, respectively. These values were superior to resveratrol and the UV filter ethylhexyl triazone (EHT) currently available on the market. In addition, all compounds demonstrated in vitro antioxidant activity and thermal stability with the decomposition at temperatures above 236 °C. In conclusion, the novel 1,3,5-triazine derivatives have emerged as new UV filters with antioxidant effect useful to prevent skin cancer.     

A novel tetrazole analogue of resveratrol is a potent anticancer agent

A series of novel tetrazole analogues of resveratrol were synthesized and evaluated for their anti-leukemic activity against an extensive panel of human cancer cell lines and against the MV4-11 AML cell line. These molecules were designed as drug-like derivatives of the resveratrol analogue DMU-212 and its cyano derivatives. Four compounds 8g, 8h, 10a and 10b exhibited LD₅₀ values of 4.60?µM, 0.02?µM, 1.46?µM, and 1.08?µM, respectively, against MV4-11 leukemia cells. The most potent compounds, 8h and 10b, were also found to be active against an extensive panel of human hematological and solid tumor cell lines; compound 8h was the most potent compound with GI₅₀ values <10?nM against more than 90% of the human cancer cell lines in the 60-cell panel. Analogues 8g, 8h, 10a and 10b were also tested for their ability to inhibit the polymerization of tubulin, and compound 8h was found to be the most potent analogue. Molecular modeling studies demonstrated that 8h binds to the colchicine binding site on tubulin. Thus, compound 8h is considered to be a lead druglike molecule from this tetrazole series of compounds.     

Synthesis of cembranoid analogues and evaluation of their potential as quorum sensing inhibitors

Natural cembranoids have shown Quorum Sensing Inhibitory (QSI) activity, but their structure–function interactions are not well understood. Thirty-four cembranoid analogues were synthesized using six natural cembranoids (1–6) previously isolated from the Colombian Caribbean octocorals Eunicea knighti and Pseudoplexaura flagellosa as lead compounds. The analogues (7–40) obtained through the selected chemical transformations were tested in vitro against the QS systems of a Chromobacterium violaceum biosensor. Half of the cembranoid analogues assayed showed superior QSI activity to the lead compounds; three (8, 13, and 18) displayed remarkable potency up to three times higher than the natural compounds. Thereby, we have synthesized a pool of cembranoid QS inhibitors that can be used in concert with natural compounds to develop antipathogenic drugs and antifouling agents.     

Rational design,synthesis and anti-proliferative evaluation of novel benzosuberone tethered with hydrazide–hydrazones

Two different series of novel analogues of benzosuberones (5a–m and 9a–w) tethered with hydrazone–hydrazides (functional group alterations: Head group to Tail group and vice versa) have been synthesized by the reaction of appropriate aldehydes with substituted hydrazides in excellent yields (87–94%) and their structures were confirmed by ¹H NMR, ¹³C NMR, ESI-MS and HRMS. The newly synthesized compounds were evaluated for anti-proliferative activity against different human cancer cell lines (HeLa, MDA MB 231, MIAPACA and IMR32). Among the synthesized compounds, six compounds 5a, 5b, 5d, 5e, 5f and 9v exhibited potent anti-proliferative activity with GI₅₀ values less than 0.01 μM against MIAPACA, MDA-MB-231 and IMR32 human cancer cell lines.     

β-Resorcylic acid derivatives with α-glucosidase inhibitory activity from Lasiodiplodia sp. ZJ-HQ1, an endophytic fungus in the medicinal plant Acanthus ilicifolius

Three new β-resorcylic acid derivatives, compounds 1–3, along with six known analogues (4–9) were isolated from an endophytic fungus Lasiodiplodia sp. ZJ-HQ₁ derived from medicinal plant Acanthus ilicifolius. Their structures were elucidated by 1D and 2D NMR spectroscopic analysis, high resolution mass spectrometric (HREIMS) data, and X-ray crystallography. The absolute configurations of compounds 1 and 2 were determined by the modified Mosher’s method. Compounds 1–7 showed more potent inhibitory effects against α-glucosidase activity than the clinical α-glucosidase inhibitor acarbose.     

Anti-enteroviral activity of new MDL-860 analogues: Synthesis,in vitro/in vivo studies and QSAR analysis

A series of 60 nitrobenzonitrile analogues of the anti-viral agent MDL-860 were synthesized (50 of which are new) and evaluated for their activity against three types of enteroviruses (coxsackievirus B1, coxsackievirus B3 and poliovirus 1). Among them, six diaryl ethers (20e, 27e, 28e, 29e, 33e and 35e) demonstrated high in vitro activity (SI > 50) towards at least one of the tested viruses and very low cytotoxicity against human cells. Compound 27e possesses the broadest spectrum of activity towards all tested viruses in the same way as MDL-860 does. The most active derivatives (27e, 29e and 35e) against coxsackievirus B1 were tested in vivo in newborn mice experimentally infected with 20 MLD₅₀ of coxsackievirus B1. Compound 29e showed promising in vivo activity (protection index 26% and 4 days lengthening of mean survival time). QSAR analysis of the substituent effects on the in vitro cytotoxicity (CC₅₀) and anti-viral activity of the nitrobenzonitrile derivatives was carried out and adequate QSAR models for the anti-viral activity of the compounds against poliovirus 1 and coxsackievirus B1 were constructed.     

Design and synthesis of pyridine-substituted itraconazole analogues with improved antifungal activities, water solubility and bioavailability

To improve antifungal activities, water solubility and bioavailability, a series of novel analogues of itraconazole-containing pyridine rings were designed and synthesized. Their antifungal activities were evaluated in vitro against six clinically important fungi by measuring the minimal inhibitory concentrations (MICs). Most of the compounds showed more potent antifungal activities than that of itraconazole. In particular, the analogues 30d, 30c, 31c, and 36d exhibited much higher solubility and bioavailability than that of itraconazole. The bioavailability of 36d (42.2%) was five times higher than that of itraconazole (8%) and was negative for genetic toxicology in the Ames test.     

Discovery of acylguanidine oseltamivir carboxylate derivatives as potent neuraminidase inhibitors

In search of novel anti-influenza agents with higher potency, a series of acylguanidine oseltamivir carboxylate analogues were synthesized and evaluated against influenza viruses (H1N1 and H3N2) in vitro. The representative compounds with strong inhibitory activities (IC₅₀ <40 nM) against neuraminidase (NA) were further tested against the NA from oseltamivir-resistant strain (H259Y). Among them, compounds 9 and 17 were potent NA inhibitors that exhibited a 5 and 11-fold increase in activity comparing with oseltamivir carboxylate (2, OC) against the H259Y mutant, respectively. Furthermore, the effect against influenza virus H259Y mutant (H1N1) replication and cytotoxicity assays indicated that compounds 9 and 17 exhibited a 20 and 6-fold increase than the parent compound 2, and had no obvious cytotoxicity in vitro. Moreover, the molecular docking studies revealed that the docking modes of compounds 9 and 17 were different from that of oseltamivir, and the new hydrogen bonds and hydrophobic interaction were formed in this case. This work provided unique insights in the discovery of potent inhibitors against NAs from wild-type and oseltamivir-resistant strains.     

Rational design and synthesis of topoisomerase I and II inhibitors based on oleanolic acid moiety for new anti-cancer drugs

Semisynthetic reactions were conducted on oleanolic acid, a common plant-derived oleanane-type triterpene. Ten rationally designed derivatives of oleanolic acid were synthesized based on docking studies and tested for their topoisomerase I and IIα inhibitory activity. Semisynthetic reactions targeted C-3, C-12, C-13, and C-17. Nine of the synthesized compounds were identified as new compounds. The structures of these compounds were confirmed by spectroscopic methods (1D, 2D NMR and MS). Five oleanolic acid analogues (S2, S3, S5, S7 and S9) showed higher activity than camptothecin (CPT) in the topoisomerase I DNA relaxation assay. Four oleanolic acid analogues (S2, S3, S5 and S6) showed higher activity than etoposide in a topoisomerase II assay. The results indicated that the C12–C13 double bond of the oleanolic acid skeleton is important for the inhibitory activity against both types of topoisomerases, while insertion of a longer chain at either position 3 or 17 increases the activity against topoisomerases by various degrees. Some of the synthesized compounds act as dual inhibitors for both topoisomerase I and IIα.     

Design,synthesis, and in vitro evaluation of novel antifungal triazoles

Twenty-nine novel triazole analogues of ravuconazole and isavuconazole were designed and synthesized. Most of the compounds exhibited potent in vitro antifungal activities against 8 fungal isolates. Especially, compounds a10, a13, and a14 exhibited superior or comparable antifungal activity to ravuconazole against all the tested fungi. Structure-activity relationship study indicated that replacing 4-cyanophenylthioazole moiety of ravuconazole with fluorophenylisoxazole resulted in novel antifungal triazoles with more effectiveness and a broader-spectrum.     

Synthesis,cytotoxicity against human oral cancer KB cells and structure–activity relationship studies of trienone analogues of curcuminoids

A general method for the synthesis of substituted (1E,4E,6E)-1,7-diphenylhepta-1,4,6-trien-3-ones, based on the aldol condensations of substituted 4-phenylbut-3-en-2-ones and substituted 3-phenylacrylaldehydes, was achieved. The natural trienones 4 and 5 have been synthesized by this method, together with the trienone analogues 9–20. These analogues were evaluated for their cytotoxic activity against human oral cancer KB cell line. The structure–activity relationship study has indicated that the analogues with the 1,4,6-trien-3-one function are more potent than the curcuminoid-type function. Analogues with meta-oxygen function on the aromatic rings are more potent than those in the ortho- and para-positions. Free phenolic hydroxy group is more potent than the corresponding methyl ether analogues. Among the potent trienones, compounds 11, 18 and 20 were more active than the anticancer drug ellipticine. All compounds were also evaluated against the non-cancerous Vero cells and it was found that compounds 11, 12 and 17 were much less toxic than curcumin (1); they showed high selectivity indices of 35.46, 33.46 and 31.68, respectively. These analogues are regarded as the potent trienones for anti-oral cancer study.     

Design,synthesis and evaluation of 1,2-benzisothiazol-3-one derivatives as potent caspase-3 inhibitors

A number of 1,2-benzisothiazol-3-one derivatives were prepared through structural modification of the original compound from high-throughput screening. Some analogues (e.g., 6b, 6r, 6s and 6w) were identified as novel and potent caspase inhibitors with IC₅₀ of nanomolar. Structure–activity relationship (SAR) studies for caspase-3 inhibition were evaluated in vitro. Molecular modeling studies provided further insight into the interaction of this class of compounds with activated caspase-3. The present small molecule caspase-3 inhibitor with novel structures different from structures of known caspase inhibitors revealed a new direction for therapeutic strategies directed against diseases involving abnormally up-regulated apoptosis.     

Synthesis and antibacterial studies of teixobactin analogues with non-isostere substitution of enduracididine

Teixobactin is a structurally and mechanistically novel antimicrobial peptide with potent activities against Gram-positive pathogens. It contains l-allo-enduracididine (End) residue which is not readily accessible. In this report, we have used convergent Ser Ligation as the key step to prepare a series of teixobactin analogues with End being substituted with its non-isostere moieties. Among these analogues, compounds T16, T27 and T29 exhibited the best antimicrobial activities against different Gram-positive bacteria with MICs ranging from 0.25 to 1.0?µM. Structure-activity relationship is also established for further development of more promising teixobactin analogues.     

Anti-melanogenesis potential of a new series of Morita-Baylis-Hillman adducts in B16F10 melanoma cell line

Melanin is a natural polymer pigment which provides skin photoprotection against ultraviolet radiation. An excessive synthesis of melanin leads to hyperpigmentation disorders. Tyrosinase catalyzes the rate limiting steps on melanogenesis. Therefore, tyrosinase inhibitors have potential applications in medicine and cosmetic fields. We carried out herein the screening of a family of cyclic Morita-Baylis-Hillman adducts (MBH) to find out their effects on tyrosinase activity and on melanogenesis in murine melanoma B16F10 cell line. Kinetic analysis of tyrosinase inhibition showed that compounds 1a (2-hydroxymethyl) cyclohex-2-enone) and 3f (diethyl (1-(6-oxocyclohex-1-en-1-yl) ethyl-phosphonate) were competitive inhibitors, whereas the compound 2b (6-oxocyclohex-1-en-1-yl) ethyl acetate) was a non-competitive one. Additionally we have found that (1a, 2b and 3f) compounds had a strong melanogenesis inhibition effect in isobutylmethylxanthine (IBMX)-treated murine melanoma B16F10 cells when tested at low and non cytotoxic dose (10–50 µM), by attenuating the melanin production, intracellular tyrosinase activity and tyrosinase expression. Thus, we suggest that these compounds could be used as effective skin-whitening agents.     

Design and synthesis of purine connected piperazine derivatives as novel inhibitors of Mycobacterium tuberculosis

A series of novel purine linked piperazine derivatives were synthesized to identify new, potent inhibitors of Mycobacterium tuberculosis. The compounds were designed to target MurB disrupting the biosynthesis of the peptidoglycan and exert antiproliferative effects. The first series of purine-2,6-dione linked piperazine derivatives were synthesized using an advanced intermediate 1-(3,4-difluorobenzyl)-7-(but-2-ynyl)-3-methyl-8-(piperazin-1-yl)-1H-purine-2,6(3H,7H)-dione hydrochloride (6) which was coupled with varied carboxylic acid chloride derivatives. Following this piperazine linked derivatives were also synthesized from 6 using diverse isocyanate partners. The anti-mycobacterial activity of the analogues was tested against Mycobacterium tuberculosis H37Rv which revealed a cluster of six analogues (11, 24, 27, 32, 33 and 34), possessed promising activity. In comparison, a set of these new compounds possessed greater potencies relative to current drugs used in the clinic such as Ethambutol. These results were also correlated with computational molecular docking analysis, providing models for strong interactions of the inhibitors with MurB providing a template for the future development of preclinical agents against Mycobacterium tuberculosis.     

Synthesis,spectroscopic and molecular docking studies on new schiff bases,nucleosides and α-aminophosphonate derivatives as antibacterial agents

New Nucleosides, analogues derived from 1, 3, 4-oxadiazole, arylidene analogues and α-aminophosphonate were prepared. Infrared (IR), elemental analysis and ¹HNMR elucidated nucleosides; arylidines and phosphonate derivatives. The prepared derivatives were purified and allowed to test against bacteria strains. Phosphonate derivative 12a showed the higher antibacterial against E. coli with inhibition zone 35 mm, P. aeruginosa with inhibition zone 30 and S. aureus with inhibition zone 22 while compounds 4, 6d, 9a, 9c and 12c showed moderate to weak activity against these bacteria species with inhibition zones ranged from 12 mm to 24 mm. The molecular docking studies was applied on compound 12a, which showed the binding at the active DNA Gyrase.     

Synthesis and evaluation of novel sulfonamide analogues of 6/7-aminoflavones as anticancer agents via topoisomerase II inhibition

A series of new sulfonamide analogues of 6/7-aminoflavones were synthesized by using molecular hybridization approach. These new sulfonamide analogues were screened for antiproliferative activity against human hepatocellular carcinoma (HepG-2), human lung cancer cell line (A-549), human colorectal adenocarcinoma (Caco-2) cancer cell lines. Compounds 5p, 5q, 5t, 5v, 5w and 5x exhibited good anticancer activity against selected cancer cell lines. These compounds were further evaluated to predict their ability to inhibit topoisomerase-II enzyme. Compound 5x has shown potent antiproliferative activity (IC₅₀ value 0.98 µM) as compared to standard drug Adriamycin (IC₅₀ = 0.94 µM) indicating that these compounds exhibits anticancer activity via inhibition of topoisomerase-II enzyme. Docking results also have supported above observations by indicating that compounds are held in the active pocket by combination of various hydrogen and hydrophobic interactions with Top II-DNA-etoposide enzyme.     

Natural abenquines and synthetic analogues: Preliminary exploration of their cytotoxic activity

In this study, we explore the cytotoxic activity of four natural abenquines (2a–d) and fourteen synthetic analogues (2e–j and 3a–h) against a panel of six human cancer cell lines using a SRB assay. It was found that most of the compounds revealed higher levels of cytotoxic activities than naturally occurring abenquines. The analogues carrying ethylpyrrolidinyl and ethylpyrimidinyl with either an acetyl group (2 h–i) or a benzoyl group (3f–g), were the most potent against all human cancer cell lines and displayed EC₅₀ between a range of 0.6–3.4 μM. Notably, of the compounds tested, compound 2i proved the most cytotoxic against both ovarian (A2780) and breast (MCF7) cells, showing EC₅₀ = 0.6 and 0.8 μM respectively. Likewise, the analogues 2i, 3f and 3 g showed strong activity against cell HT29 with EC₅₀ = 0.9 μM for these compounds.     

Discovery and evaluation of novel nitrodihydroimidazooxazoles as promising anti-tuberculosis agents

New analogues of antitubercular drug Delamanid were prepared, seeking drug candidates with enhanced aqueous solubility and high efficacy. The strategy involved replacement of phenoxy linker proximal to the 2-nitroimidazooxazole of Delamanid by piperidine fused 5 or 6-membered ring heterocycles (ring A). The new compounds were all more hydrophilic than Delamanid, and several class of analogues showed remarkable activities against M. bovis. And among these series, the tetrahydro-naphthyridine-linked nitroimidazoles displayed excellent antimycobacterial activity against both replicating (MABA) and nonreplicating (LORA) M. tb H37Rv and low cytotoxicity. Compared to Delamanid, these new compounds (6, 7, 45) demonstrated dramatically improved physicochemical properties and are suitable for further in vitro and in vivo evaluation.