Hassan M. Faidallah

Synthesis and Biological Evaluation of Some 2,4,5- Trisubstituted Thiazole Derivatives as Potential Antimicrobial and Anticancer Agents

We report on the synthesis and biological evaluation of two series of 2,4,5‐polysubstituted thiazoles comprising the acid hydrazide functionality and some derived pharmacophores known to contribute to various chemotherapeutic activities. All newly synthesized compounds were subjected to in‐vitro antibacterial and antifungal screening. Of the compounds tested, 13 derivatives displayed inhibitory effect on the growth of three Gram‐positive strains while they lack activity against Gram‐negative bacteria. Moreover, four compounds were able to exert antifungal activity against C. albicans. Potential antibacterial and antifungal activities were linked to the thiosemicarbazide function 6a–f and those substituted with both the thioureido and thiosemicarbazide moieties 12a–f. Compounds 6f and 12f (R = 4‐F‐C6H4) could be considered as the most active members in this investigation with a broad spectrum of antibacterial activity against three types of Gram‐positive bacteria, together with an appreciable antifungal activity against C. albicans. Compounds 6d, 6f, and 12f were twice as active as ampicillin against B. subtilis. The best antifungal activity was shown by compound 6d 50% less active than clotrimazole. 17 compounds were selected and tested for their preliminary in‐vitro anticancer activity according to the current one‐dose protocol of the NCI. Three cell lines, non‐small cell lung cancer Hop‐92, ovarian cancer IGROV1, and melanoma SK‐MEL‐2, exhibited some sensitivity against most of the tested compounds. Compound 12f proved to be the most active anticancer member with a broad spectrum of activity against most of the tested subpanel tumor cell lines. Consequently, 12f was carried over to be tested in the five‐dose assay.

3-Methyl-2-(4-substituted phenyl)-4,5-dihydronaphtho[1,2-c]-pyrazoles : Synthesis and in-vitro Biological Evaluation as Antitumour Agents

The synthetic strategies and characterization of some novel derivatives of 3‐methyl‐2‐(4‐substituted phenyl)‐4,5‐dihydronaphtho[1,2‐c]pyrazoles carrying different pharmacophores and heterocyclic rings that are relevant to potential antitumour and cytotoxic activities are described. The antitumour activities of the newly synthesized compounds were evaluated according to the protocol of the National Cancer Institute (NCI) in‐vitro disease‐oriented human cells screening panel assay. The results revealed that six compounds, namely 6, 8, 11, 15, 17 and 18; displayed promising in‐vitro antitumour activity in the 60‐cell lines assay. The sulfonylthioureido group emerged as the most favourable pharmacophore. Incorporating such thioureido counterpart into the 6‐membered 1,3‐thiazinan‐5‐one resulted in better antitumour activities than those displayed by the 5‐membered thiazoles and the 6‐membered 1,3‐thiazinan‐4‐one ring systems. Further ring expansion led to a total loss of the antitumour activity. The analog 18, 3‐benzyl‐2‐[4‐(3‐methyl‐4,5‐dihydronaphtho‐[1,2‐c]pyrazol‐2‐yl)‐benzenesulfonylimino]‐1,3‐thiazinan‐5‐one, proved to be the most active member identified in this series of compounds (GI50, TGI, and LC50 MG‐MID values of 34.7, 85.1 and 97.7 μM, respectively). The differential cytotoxicity of the six active compounds to cancer and normal cells was studied utilizing the standard MTT cell viability assay. Compounds 17 and 18 were totally selective for the breast cancer cell line MCF7 (IC50 8.5 and 4.7 μM), without exerting any inhibitory effect on the normal breast cell line MCF‐10A at the concentration level used (25 μM).

Synthesis and spectral characterization of novel 1,3,4-oxadiazole and 1,2,4-triazole derivatives: Synthesis for potential pharmacological activities

Oxadiazole derivatives ( 3a , b ) and ( 4a , b ) were obtained in a good yield by the reaction of the benzylidene derivatives ( 2a , b ) with acetic anhydride and yellow mercuric oxide respectively. Cyclodesulfurization of the thiosemicarbazide derivatives ( 5a-c ) with yellow mercuric oxide afforded the oxadiazoles ( 7a-c ). On the other hand, reaction of ( 5a-c ) with sodium hydroxide gave the triazoles ( 6a-c ). The structures of the isolated products were fully determined by spectral methods.

Bifunctional ethyl 2-amino-4-methylthiazole-5-carboxylate derivatives: Synthesis and in vitro biological evaluation as antimicrobial and anticancer agents

Thirty thiazole compounds bearing chemotherapeutically-active pharmacophores were synthesized and evaluated for their preliminary in vitro antimicrobial and anticancer activities. Nineteen compounds displayed obvious antibacterial potential, with special bactericidal activity against Gram positive bacteria, whereas, nine analogs showed moderate to weak antifungal activity against Candida albicans. The analog 12f proved to be the most active antimicrobial member identified in this study being comparable to ampicillin and gentamicin sulfate against Staphylococcus aureus and Bacillus subtilis, together with a moderate antifungal activity. Additionally, nine derivatives were tested for their preliminary in vitro anticancer activity according to the current one-dose protocol of the NCI. Compound 9b revealed a broad spectrum of anticancer activity against 29 out of the tested 60 subpanel tumor cell lines. Collectively, compounds 4, 9b, 10b and 12f could be considered as promising dual anticancer antibiotics.

Synthesis, characterization and spectroscopic behavior of novel 2-oxo-1,4-disubstituted-1,2,5,6-tetrahydrobenzo[h]quinoline-3-carbonitrile dyes

Two synthetic pathways were adopted to synthesize the target 2-oxo-1,4-disubstituted-1,2,5,6-tetrahydro-benzo[h]quinoline-3-carbonitriles. Structure of the synthesized compounds has been characterized based on FT-IR, (1)H NMR, (13)C NMR and elemental analyses. UV-Vis and fluorescence spectroscopy measurements provided that all compounds are good absorbent and fluorescent. Fluorescence polarity study demonstrated that these compounds were sensitive to the polarity of the microenvironment provided by different solvents. In addition, spectroscopic and physicochemical parameters, including singlet absorption, extinction coefficient, Stokes shift, oscillator strength and dipole moment were investigated in order to explore the analytical potential of synthesized compounds.

3-cyano-8-methyl-2-oxo-1,4-disubstituted-1,2,5,6,7,8-hexahydroquinolines: synthesis and biological evaluation as antimicrobial and cytotoxic agents.

The synthesis, in vitro antimicrobial and cytotoxic activities of some novel hexahydroquinolines supported with various pharmacophores are described. The results revealed that 18 compounds displayed pronounced activity against Staphylococcus aureus and Escherichia coli bacteria beside a moderate antifungal activity. Compound 25 is the most active candidate with equipotency to ampicillin against S. aureus, E. coli and Pseudomonas aeruginosa, together with an obvious antifungal activity. Additionally, 12 compounds showed remarkable cytotoxic efficiency against human colon carcinoma HT29, hepatocellular carcinoma Hep-G2 and Caucasian breast adenocarcinoma MCF7 cell lines. Among these, the analogs 22 and 25 proved to be the most active cytotoxic members. Collectively, the results would suggest that compounds 22 and 25 could be considered as possible dual antimicrobial-anticancer agents.

Total synthesis of cyclic heptapeptide Rolloamide B.

The first total synthesis of Rolloamide B, a cyclic proline-enriched heptapeptide, is reported. This work features solution phase benzotriazole-mediated peptide synthesis ligating native amino acids.

Synthesis and in vitro antitumor and antimicrobial activity of some 2,3-diaryl-7-methyl-4,5,6,7-tetrahydroindazole and 3,3a,4,5,6,7-hexahydroindazole derivatives

The synthesis of a series of 2,3-diaryl-7-methyl-4,5,6,7-tetrahydroindazole and 3,3a,4,5,6,7-hexahydroindazole derivatives substituted with various biologically-active function groups with anticipated chemotherapeutic activity is described. 4-(7-methyl-3-aryl-3,3a,4,5,6,7-hexahydro-indazol-2-yl)benzenesulfonamides 2a–c, which were employed as key intermediates in this study, were synthesized by cyclocondensation of 6-arylidene-2-methylcyclohexanones 1a–c with 4-hydrazinobenzenesulfonamide hydrochloride. A detailed discussion of the reactions utilized in the preparation of the intermediate and target compounds is reported, and the structures of the newly synthesized compounds were substantiated with IR, 1H and 13C NMR spectral data and elementary microanalyses. Twenty of the newly synthesized compounds were selected by National Cancer Institute (NCI), Maryland, USA, to be evaluated for their antitumor activity and the results revealed that six compounds 3c, 4d,e, 5a,d and 8c exhibited broad spectrum of antitumor activity against most of the tested tumor cell lines. In addition, the in vitro antibacterial and antifungal activities of a number of the target compounds were also tested using the Agar-diffusion method. Some of these compounds have shown significant antibacterial and mild to moderate antifungal activities.

Synthesis and biological evaluation of some novel urea and thiourea derivatives of isoxazolo[4,5-d]pyridazine and structurally related thiazolo[4,5-d]pyridazine as antimicrobial agents

This study reports the synthesis of some novel isoxazolo[4,5-d]pyridazines and structurally related thiazolo[4,5-d]pyridazines, and their biological evaluation as antimicrobial agents. The proposed compounds were designed to contain pharmacophores such as urea, thiourea, sulfonylurea (thiourea) and some derived functionalities that are believed to contribute to the anticipated biological activities. The results revealed that 25 compounds displayed broad spectrum of antibacterial activity, with greater inhibitory effect on the growth of the tested Gram positive strains compared to Gram negative ones. Moreover, 14 compounds were able to produce appreciable growth inhibitory activity against Candida albicans fungus when compared to Clotrimazole. Most of the tested isoxazolo[4,5-d]pyridazines displayed better antimicrobial profile than their corresponding thiazolo[4,5-d]pyridazine congeners. Four compounds namely, p-(3,7-dimethyl-4-oxo-4H-isoxazolo [4,5-d]pyridazine-5-yl)benzenesulfonylthioureas (11c–d), 3-substituted-2-[p-(3,7-dimethyl-4-oxo-4H-isoxazolo[4,5-d]pyridazine-5-yl)-benzene-sufonylimino]-4-oxothiazolidines (13d) and p-(2,7-dimethyl-4-oxo-4H-thiazolo[4,5-d]pyridazin-5-yl)benzenesulfonylthiourea (24c) were found to be most active antimicrobial members in present study.

Synthesis, antimalarial properties and 2D-QSAR studies of novel triazole-quinine conjugates

Click chemistry technique led to novel 1,2,3-triazole-quinine conjugates 8a-g, 10a-o, 11a-h and 13 utilizing benzotriazole-mediated synthetic approach with excellent yields. Some of the synthesized analogs (11a, 11d-h) exhibited antimalarial properties against Plasmodium falciparum strain 3D7 with potency higher than that of quinine (standard reference used) through in vitro standard procedure bio-assay. Statistically significant BMLR-QSAR model describes the bio-properties, validates the observed biological observations and identifies the most important parameters governing bio-activity.