Ali Kh. Khalil

A Facile Synthesis of Some New Thiazolo[3, 2]pyridines Containing Pyrazolyl Moiety and Their Antimicrobial Activity

Abstract Condensation of 2-cyanomethyl-4-thiazolinone 1 with 1,3-diphenyl-pyrazole-4-carboxaldehyde 2 in ethanol containing a few drops of piperidine yielded the novel methylene derivative 3 . Compound 3 was refluxed with malononitrile to give the corresponding thiazolo[ [3] , [2] ]pyridine derivative 5 . Also, treatment of compound 3 with benzylidenemalononitriles gave the thiazolo[ [3] , [2] ]pyridine derivatives 6a–e . Refluxing of compound 6d with triethyl orthoformate furnished the ethoxymethylideneamino derivative 7 . Formic acid and malononitrile were reacted with compound 6d to produce thiazolo[ [3] , [2] ][ [1] , [8] ]naphthyridine derivative 8 and 11 , respectively. Condensation of 2 with cyanoacetohydrazide in ethanol containing piperidine as catalyst gave the hydrazone derivative 12 which, on treatment with salicyaldehyde and 2-cyano-3-(4-fluorophenyl)acrylic acid ethyl ester, yielded the novel chromene 13 and pyridinone 14 , respectively. Structures of the synthesized compounds have been established by elemental analysis and spectral data. Compounds 3 , 5 , 6a–d , 8 , 11 , 13 , and 14 have been screened for antimicrobial activities.

Studies of Thiazolopyridines, Part 6: Synthesis and Antimicrobial Evaluation of Some Novel Thiazolo[3,2-a] Pyridine and Thiazolo[2′,3′:6,1]-pyrido[2,3-d]pyrimidine Derivatives

Condensation of thiazolinone 1 with aromatic aldehydes yielded the corresponding methylidene derivatives 2a–f. Cyclization of compounds 2a–f with arylidenemalononitrile 3 (1:1 molar ratio) in ethanol in the presence of piperidine furnished the novel thiazolo[3,2-a]pyridines 5a–v, via Michael adduct 4. Compounds 5p, r were cyclized with malononitrile in the presence of piperidine to yield thiazolo[3,2-a][1,8]naphthryidines 7a, b. Thiazolo-[2′,3′:1,6]pyrido[2,3-d]pyrimidine 9a–cwere obtained by cyclization of compounds 5c, p, r with formic acid. The structure of the synthesized compounds was established by analytical and spectral data. Also, some of the synthesized compounds were screened for antimicrobial activity in vitro.

N- vs. S-PTC Alkylation of 5-Carboethoxy-2-thiouracil And Its Reactivity Towards Some Nucleophilic Reagents

The reactivity of 5-carboethoxy-2-thiouracil (1) toward alkylation by different organohalogen compounds under phase-transfer catalysis (PTC) conditions has been investigated to give S-monoalkylated products and/or simultaneous S- and N-dialkylated products. Also, nucleophilic additions of methylmagnesium iodide, hydroxylamine, and hydrazine to 5-carbethoxy-2-thiouracil (1) have been investigated. The structures of all products have been confirmed by elemental analysis and spectral data.

PTC-ALKYLATION AND MICHAEL ADDITION OF INDANONES; SYNTHESIS OF 2-SUBSTITUTED INDANONES

Abstract The reactivity of indan-1-one (1a) and or indan-1,3-dione (1b) towards alkylation in the absence or presence of carbon disulphide under phase transfer catalysis (PTC) conditions has been investigated to give indanone derivatives 2–9. Michael addition of (1a,b) to α,β-unsaturated carbonyl compounds under the same FTC conditions yielded the adducts 10–16.

Design, synthesis of new pyrimidine derivatives as anticancer and antimicrobial agents

ABSTRACT A new series of 6-aryl-5-cyano thiouracil derivatives were synthesized. Cyanouracil 1 was condensed with monochloroacetic acid and different aldehydes to give thiazolopyrimidine 2. On the other hand, treatment of cyanouracil 1 with 2-chloro-N-substituted-phenylac etamide afforded 4. Hydrazinolysis of 6 afforded the hydrazino derivatives 7 which upon reaction with different electrophilic reagents such as acetic anhydride, benzoyl chloride, and carbon disulfide yielded pyrimidine derivatives 8–15. Some of the new derivatives were explored for their antimicrobial activities. Compounds 7 and 9 have a promising activity, relatively equipotent to the reference drug. All of the new synthesized compounds were tested in vitro for their antiproliferative activities against HePG-2 and MCF-7 cell lines. Compounds 7, 9, and 2d displayed potent growth inhibitory effect toward the two cell lines more than the standard drug 5-FU. Furthermore, a docking study of the most active compounds was performed with thymidylate synthase enzyme. GRAPHICAL ABSTRACT

Phase-Transfer Catalyzed Alkylation and Acylation of 2-Mercapto-5-Methyl-1H-Benzimidazole

Solid/liquid phase-transfer catalyzed alkylation and acylation of 2-mercaptobenzimidazole at 25°C by different organohalogen reagents in the presence of tetrabutylammonium bromide as a catalyst underwent, exclusively, S-monoalkylation and N-monoacylation or S-and N-dialkylation, cycloalkylation, and S-and N-diacyla-tion depending on the nature of alkylating and acylating agents.

Utility of chloroacetonitrile in construction of some hitherto novel pyrazole and thiazole derivatives

Abstract2-(-Piperidin-1-yl) acetamide (2) was easily prepared by reacting chloroacetonitrile with piperidine. Furthermore, (2) was allowed to react with different aromatic aldehydes to afford novel arylidene derivatives (3a,b). Unexpectedly, 2-oxo-4-hydroxy-thiazole (5) was obtained instead of 2-(piperidin-1-yl-methylene) thiazolidin-4-one (4) when (2) was treated with mercaptoacetic acid under fusion conditions. Subsequent treatment of (5) with aromatic aldehydes and either malononitrile or cyanoacetamide (1:1:1 molar ratios) produced the hitherto unknown pyrano[2,3-d] thiazole derivatives (6a,b) and (7). Novel pyrazole derivatives (8a, b) and (9) were synthesized upon cyclocondensation of (2) with aromatic aldehydes and hydrazine hydrate. Unfortunately, attempts to prepare novel isoxazole derivatives by utilizing hydroxylamine instead of hydrazine hydrate following the previous procedure were failed. Surprisingly, the uncyclized products (10a,b) were obtained rather than 3-hydroxy-4-piperidinyl-isoxazole (11a,b). Upon refluxing thiosemicarbazide with (2) and aromatic aldehydes under the same conditions, pyrazolinone carbothioamides (12), (13) and (14a-c) were obtained.

Eco-friendly Synthesis of Pyrido[2,3-d]pyrimidine Analogs and Their Anticancer and Tyrosine Kinase Inhibition Activities

BACKGROUND One of the promising scaffolds in drug discovery is the fused pyrimidine derivatives. OBJECTIVE AND METHOD Efficient synthesis of a novel series of 18 new 1,8-naphthyridine-3-carbonitrile, 2-amino pyrido[2,3-d]pyrimidine derivatives via multi-component reactions of aromatic aldehydes, active methylene, and an aromatic amine under microwave irradiation and evaluation of their anticancer activity and possible mechanisms. RESULTS Only compounds 5 (a-c) had a significant antiproliferative activity in hepatic HepG2 cells at submicromolar concentration (7.5-10 µM). Similarly, only compound 11 (a-c) had a significant activity in breast MCF7 cells at (4-7 µM). Derivatives with one methoxyphenyl substitution (5a and 11a) were not different from derivatives having dimethoxyphenyl substitution (5b and 11b). However, thiophene substitution (5c and 11c) enhanced the anticancer activity in both cells lines examined by 25% in HepG2 and by ~45% in MCF7 cells compared to a and b derivatives. All compounds were safe to both normal human lung cells (WI-38) and RBCs at concentrations up to 40 mM. The antiproliferative activity of compounds 5 (a-c) in HepG2 could be attributed to an induction of intrinsic apoptotic pathway as evidenced from the induction of initiator caspase 9 by ~ 4 folds. While, the activity of compounds 11 (a-c) could be attributed to their potential to inhibit tyrosine kinases (TK) by up to 85%. The IC50 of derivative 11c against TK was at 173 nM. CONCLUSION The present study reported that derivatives 5 and 11 have merit for further investigation as anticancer and TK inhibitors.

Novel Tetrahydrobenzo [b] Thiophene Compounds Exhibit Anticancer Activity through Enhancing Apoptosis and Inhibiting Tyrosine Kinase

BACKGROUND Developing new chemotherapeutic agents with molecular targets, larger margin of safety against normal cells and low cost is the target many scientists try to achieve. OBJECTIVE The present study was undertaken to investigate the anticancer activity of a novel series of thiophene compounds and the molecular mechanisms associated. METHOD A series of novel heterocyclic compounds including pyrimidine derivatives (2, 3, 4, 5 8, 11, 12, 13, 14, and 15), thiophene derivatives (6, 7, and 10) and oxoisothiazolidine derivative (9) was synthesized from 4,5,6,7- tetrahydrobenzo[b] thiophene (1). The newly synthesized derivatives along with the parent compound were evaluated for their anticancer activity against human HepG2, MCF7 and HCT116 cell lines and compared to doxorubicin as a reference drug. RESULTS Compound 7 was very selective in targeting only the colon cells. Compounds 1, 5, and 12 showed strong cytotoxic activities against the 3 cell lines at 6-16 µM without any apparent toxicity to the normal fibroblasts WI-38. They had DNA affinity at 29-36 µM. The three compounds enhanced apoptosis to varying degrees elevating the expression of Bax, caspase 9 and caspase 3 in HepG2. Compound 5 was the most potent analogue and was superior to the standard drug used in upregulating the apoptotic genes and inhibiting tyrosine kinase at 1 µM. The IC50 value for compound 5 against TK was 296 nM. CONCLUSION Taken together, this study presents some thiophene scaffolds as auspicious hits for further optimization as specific antiproliferative agents against cancer cells and promising tyrosine kinase inhibitors at nanomolar concentrations.