Sherif A. F. Rostom

Design and synthesis of some thiazolyl and thiadiazolyl derivatives of antipyrine as potential non-acidic anti-inflammatory, analgesic and antimicrobial agents ☆

The synthesis of two groups of structure hybrids comprising basically the antipyrine moiety attached to either polysubstituted thiazole or 2,5-disubstituted-1,3,4-thiadiazole counterparts through various linkages is described. Twelve out of the newly synthesized compounds were evaluated for their anti-inflammatory activity using two different screening protocols; namely, the formalin-induced paw edema and the turpentine oil-induced granuloma pouch bioassays, using diclofenac Na as a reference standard. The ulcerogenic effects and acute toxicity (ALD(50)) values of these compounds were also determined. Meanwhile, the analgesic activity of the same compounds was evaluated using the rat tail withdrawal technique. Additionally, the synthesized compounds were evaluated for their in vitro antimicrobial activity. In general, compounds belonging to the thiazolylantipyrine series exhibited better biological activities than their thiadiazolyl structure variants. Collectively, compounds 6, 10, 26, and 27 proved to display distinctive anti-inflammatory and analgesic profiles with a fast onset of action. All of the tested compounds revealed super GI safety profile and are well tolerated by the experimental animals with high safety margin (ALD(50)>3.0 g/kg). Meanwhile, compounds 7, 10, 11, and 23 are considered to be the most active broad spectrum antimicrobial members in this study. Compound 10 could be identified as the most biologically active member within this study with an interesting dual anti-inflammatory analgesic and antibacterial profile.

Azole antimicrobial pharmacophore-based tetrazoles: synthesis and biological evaluation as potential antimicrobial and anticonvulsant agents.

The azole pharmacophore is still considered a viable lead structure for the synthesis of more efficacious and broad spectrum antimicrobial agents. Potential antibacterial and antifungal activities are encountered with some tetrazoles. Therefore, this study presents the synthesis and antimicrobial evaluation of a new series of substituted tetrazoles that are structurally related to the famous antimicrobial azole pharmacophore. A detailed discussion of the structural elucidation of some of the newly synthesized compounds is also described. Antimicrobial evaluation revealed that twenty compounds were able to display variable growth inhibitory effects on the tested Gram positive and Gram negative bacteria with special efficacy against the Gram positive strains. Meanwhile, six compounds exhibited moderate antifungal activity against Candida albicans and Aspergillus fumigatus. Structurally, the antibacterial activity was encountered with tetrazoles containing a phenyl substituent, while the obtained antifungal activity was confined to the benzyl variants. Compounds 16, 18, 24 and 27 were proved to be the most active antibacterial members within this study with a considerable broad spectrum against all the Gram positive and negative strains tested. A distinctive anti-Gram positive activity was displayed by compound 18 against Staphylococcus aureus that was equipotent to ampicillin (MIC 6.25 microg/mL). On the other hand, twelve compounds were selected to be screened for their preliminary anticonvulsant activity against subcutaneous metrazole (ScMet) and maximal electroshock (MES) induced seizures in mice. The results revealed that five compounds namely; 3, 5, 13, 21, and 24 were able to display noticeable anticonvulsant activity in both tests at 100 mg/kg dose level. Compounds 5 and 21 were proved to be the most active anticonvulsant members in this study with special high activity in the ScMet assay (% protection: 100% and 80%, respectively).

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.

Polysubstituted pyrazoles, part 6. Synthesis of some 1-(4-chlorophenyl)-4-hydroxy-1H-pyrazol-3-carbonyl derivatives linked to nitrogenous heterocyclic ring systems as potential antitumor agents☆☆☆

The synthesis of two novel series of 1-(4-chlorophenyl)-4-hydroxy-1H-pyrazoles linked to either polysubstituted 1H-pyrazole counterparts through a carbonyl bridge, or to some biologically-active nitrogenous heterocycles by an amide linker, is described. Ten of the newly synthesized compounds were selected by the National Cancer Institute (NCI) in vitro disease-oriented antitumor screening to be evaluated for their antitumor activity. The most active six compounds 2, 3, 6, 7, 13 and 14 revealed a significant broad spectrum of antitumor potential against most of the tested subpanel tumor cell lines at the GI(50) and TGI levels, together with a mild cytotoxic (LC(50)) activity. The pyrazolinedione analog 7 displayed remarkable growth inhibition and cytostatic effects (GI(50) and TGI MG-MID values 0.67 and 53.8microM, respectively). Compounds 13 (GI(50), TGI, and LC(50) MG-MID values 0.08, 30.9 and 93.3microM) and 14 (GI(50), TGI, and LC(50) MG-MID values 0.36, 8.78 and 69.3microM, respectively) proved to be the most active antitumor members identified in this study.

Synthesis and biological evaluation of some novel polysubstituted pyrimidine derivatives as potential antimicrobial and anticancer agents.

Synthesis and evaluation of the antimicrobial and cytotoxic activity of two series of polysubstituted pyrimidines comprising the thioether functionality and other pharmacophores, reported to contribute to various chemotherapeutic activities are described. All newly synthesized compounds were subjected to in‐vitro antibacterial and antifungal screening. Out of the compounds tested, 18 derivatives displayed an obvious inhibitory effect on the growth of the tested Gram‐positive and Gram‐negative bacterial strains, with special effectiveness against the Gram‐positive strains. Compounds 1, 2, 6, 7, 9, 10, 11, 21, and 24 revealed remarkable broad antibacterial spectrum profiles. Among those, compounds 1, 2, 6, 7, 9, and 24 exhibited an appreciable antifungal activity against C. albicans. Compound 2 proved to be the most active antimicrobial member identified here as it showed twice the activity of ampicillin against B. subtilis and the same activity of ampicillin against M. Luteus and P. aeruginosa together with a moderate antifungal activity. Further, eleven analogs were evaluated for their in‐vitro cytotoxic potential utilizing the standard MTT assay against a panel of three human cell lines: breast adenocarcinoma MCF7, hepatocellular carcinoma HePG2, and colon carcinoma HT29. The obtained data revealed that six of the tested compounds 1, 3, 7, 12, 13, and 15 showed a variable degree of cytotoxic activity against the tested cell lines at both the LC50 and LC90 levels. Compound 7 proved to be the most active cytotoxic member in this study with special effectiveness against the colon carcinoma HT29 and breast cancer MCF7 human cell lines for LC50 and LC90. Thus, compounds 1 and 7 could be considered as possible dual antimicrobial‐anticancer agents.

Synthesis and Biological Evaluation of Some Polymethoxylated Fused Pyridine Ring Systems as Antitumor Agents

A series of 3,5‐bis(arylidene)‐4‐piperidones like chalcone analogues carrying variety of methoxylated aryl groups, pyrazolo[4,3‐c]pyridines, pyrido[4,3‐d]pyrimidines, and pyrido[3,2‐c]pyridines, carrying an arylidene moiety, and some pyrano[3,2‐c]pyridines, like flavone and coumarin isosteres, were synthesized and screened for their in‐vitro antitumor activity at the National Cancer Institute (NCI, USA). The tested compounds 7, 9, 10, 12, 13, 15, 17, and 19 exhibited a broad spectrum of antitumor activity. Compounds belonging to the pyrazolo[4,3‐c]pyridine series proved to be more active than those of the pyrido[3,2‐c]pyridine and pyrano[3,2‐c]pyridine analogues, in which the monomethoxylated derivatives showed better antitumor activity when compared with their corresponding dimethoxylated congeners. Compound 7 is considered to be the most active member identified in this study with a broad spectrum of activity against 22 different tumor cell lines belonging to the nine subpanels employed, and a particular effectiveness against the breast cancer T‐47D cell line (GI 54.7%). The pyrano[3,2‐c]pyridine heterocyclic system 19 proved to be the most active antitumor agent among the six‐membered fused pyridines, with variable activity against 18 different tumor cell lines, and special activity against the non‐small cell lung cancer Hop‐92 and ovarian cancer OVCAR‐4 cell lines (GI values 63.9 and 48.5%, respectively).

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 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.