Ahmed M. Alafeefy

Synthesis of some new pyrazolo[3,4-d]pyrimidine derivatives of expected anticancer and radioprotective activity

On the account of the reported anticancer activity of pyrazolo[3,4-d]pyrimidines, a new series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized and tested for in-vitro anticancer activity against Ehrlich Ascites Carcinoma (EAC) cell line. Moreover, one of the target products was evaluated for in-vivo radioprotective activity. The reaction of o-aminoester 1 with benzylamine in presence of triethylorthoformate yielded the corresponding 5-benzylpyrazolopyrimidine derivative 2. The N-amino derivative 3 was used to synthesize new derivatives of pyrazolopyrimidines 4-7. The corresponding 1,3,4-oxadiazolopyrazolopyrimidine derivatives 12 and 14 were obtained via reaction of compound 9 with reagent 10 and/or triethylorthoformate. Thiophosgenation of compound 1 furnished the corresponding 5-isothiocyanate derivative 15, which was reacted with o-phenylenediamine, thiosemicarbazide and anthranilic acid to give benzimidazolopyrazolopyrimidine, 17, pyrazolotriazolopyrimidine, 19 and pyrazolopyrimidobenzoxazine, 20 respectively. The structures of the synthesized compounds were confirmed by microanalyses, IR, NMR, and mass spectral data. Compounds 2 and 9 showed intermediate anticancer activity compared to doxorubicin as positive control with IC50 values of 90 and 100 microg/ml, respectively. On the other hand, compound 5 showed significant radioprotective effect.

Novel quinolines and pyrimido[4,5-b]quinolines bearing biologically active sulfonamide moiety as a new class of antitumor agents

Some novel quinolines and pyrimido[4,5-b]quinolines have been synthesized. The structures of which were confirmed by elemental analyses and spectral data. All the target compounds were subjected to in-vitro antitumor activity against Ehrlich Ascites Carcinoma (EAC) cells. Compounds 24, 19 and 12 showed higher activity with IC(50) values (5.5, 6.9, 7 microg/ml) when compared with Doxorubicin as a reference drug (IC(50) value 38 microg/ml).

Synthesis, analgesic and anti-inflammatory evaluation of some novel quinazoline derivatives

Two series of some new 2,4,6-trisubstituted-quinazoline derivatives were prepared and screened for their analgesic, anti-inflammatory activity and acute toxicity. Four compounds were more potent analgesic agents than the reference drug Indomethacin and thirteen compounds showed significant anti-inflammatory activity. Seven compounds showed combined ability to inhibit both pain and inflammation. Compounds tested for acute toxicity showed no toxic symptoms or mortality rates 24 h post-administration implying their good safety margin.

Carbonic anhydrase inhibitors: Benzenesulfonamides incorporating cyanoacrylamide moieties are low nanomolar/subnanomolar inhibitors of the tumor-associated isoforms IX and XII

A series of benzenesulfonamides incorporating cyanoacrylamide moieties (tyrphostine analogues) have been obtained by reaction of sulfanilamide with ethylcyanoacetate followed by condensation with aromatic/heterocyclic aldehydes, isothiocyanates or diazonium salts. The new compounds have been investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4. 2.1.1), and more specifically against the cytosolic human (h) isoforms hCA I and II, as well as the transmembrane, tumor-associated ones CA IX and XII, which are validated antitumor targets. Most of the new benzenesulfonamides were low nanomolar or subnanomolar CA IX/XII inhibitors whereas they were less effective as inhibitors of CA I and II. The structure-activity relationship for this class of effective CA inhibitors is also discussed. Generally, electron donating groups in the starting aldehyde reagent favored CA IX and XII inhibition, whereas halogeno, methoxy and dimethylamino moieties led to very potent CA XII inhibitors.

Synthesis, Analgesic and Anti-Inflammatory Evaluation of Some New 3H-Quinazolin-4-one Derivatives

In this study, we have synthesized a series of 3H‐quinazolin‐4‐ones in order to obtain new compounds with potential analgesic and anti‐inflammatory activity. The structures of the newly synthesized compounds were confirmed by means of infrared, nuclear magnetic resonance and mass spectroscopy. Some compounds were evaluated for their analgesic and anti‐inflammatory activities by writhing and carrageenan‐induced rat paw edema tests, respectively. In comparison to the standard drug indomethacine, compounds 4, 6c, 12–14, 16, 18, 19, and 22 induced significant reduction in the writhing response while compounds 6c, 12, 14, 16, 18, and 22 produced a good dose‐dependent anti‐inflammatory activity. The best dual analgesic / anti‐inflammatory relative activity was observed with compounds 6c, 14, 16, 18, and 22.

Synthesis and biological evaluation of 2-amino-7,7-dimethyl 4-substituted-5-oxo-1-(3,4,5-trimethoxy)-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile derivatives as potential cytotoxic agents

A large number of antimitotic drugs, derived from natural sources or chemically synthesized, have been identified and shown to interfere with the tubulin system. Inhibition of tubulin polymerization is among the important targets useful in the cancer therapy. The present work reports the synthesis of some novel quinoline derivatives bearing a trimethoxyphenyl moiety. The trimethoxybenzene moiety has been reported to be crucial to obtain relevant cytotoxic and antitubulin responses. All the newly synthesized compounds were evaluated for their in vitro anticancer activity. Several compounds showed interesting cytotoxic activities compared to the used reference drug.

Discovering some novel tetrahydroquinoline derivatives bearing the biologically active sulfonamide moiety as a new class of antitumor agents.

The present article describes the synthesis of some novel 4-(2-amino-3-cyano-4-(substituted-aryl)-5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl)benzenesulfonamide (23-41) starting with 4-(3-oxo-cyclohex-1-enylamino)benzenesulfonamide (3). All the newly synthesized compounds were evaluated for their in vitro antitumor activity. Compounds 32, 25, 41, 35, 33, and 37 with IC50 values (2.5, 3, 5, 10, 12, and 12.5 microg/mL) are more potent and efficacious than Doxorubicin (CAS-23214-92-8) as reference drug with (IC50 value=37.5 microg/mL). Also, compounds 28, 30, 31, and 34 (with IC50 values=25 microg/mL) are nearly as active as Doxorubicin.

Inhibition studies of quinazoline-sulfonamide derivatives against the γ-CA (PgiCA) from the pathogenic bacterium, Porphyromonas gingivalis

Abstract Carbonic anhydrases (CAs, EC 4.2.1.1) began to be investigated in detail in pathogenic bacteria, in the search for antibiotics with a novel mechanism of action, since it has been demonstrated that in many bacteria CAs are essential for the life cycle of the organism. The presence of CAs in pathogenic bacteria allows the development of anti-infectives with a new mechanism of action, less explored to date. Here, novel quinazoline derivatives crowned with sulfonamide functionality at position-2 were tested for their ability to inhibit the bacterial γ-CA (PgiCA), identified in the genome of Porphyromonas gingivalis. Six compounds were highly effective, nanomolar inhibitors of the pathogenic enzyme γ-PgCA. Three of them were also highly effective sub-nanomolar inhibitors of the cytosolic human isoform II (hCAII). The best γ-PgCA inhibitor was compound 8c, with a KI of 3.53 nM and selectivity ratio of 24.5 and 24.8 against hCA I and hCA II, respectively. Many of these new compounds showed a high selectivity for bacterial enzyme respect to the mammalian CA isoforms (hCAI and hCAII). These results suggest that sulfonamides with quinazoline scaffold could be considered as suitable candidates for further derivatization to better understand the role of bacterial CAs in pathogenesis.

Quinazoline-tyrphostin as a new class of antitumor agents, molecular properties prediction, synthesis and biological testing

A new series of substituted quinazolin-4-(3H)-one-tyrphostin derivatives was prepared and screened for their cytotoxic activity against three tumor cell lines, namely human breast cancer cell line (MCF-7), human cervical cancer cell line (HeLa) and human hepatocellular liver carcinoma cell line (HepG2) using the colorimetric MTT assay. Among the current series, 10 compounds exhibited remarkable in vitro antiproliferative activity against the three tested cell lines with the IC(50) values ranging from 0.009 to 0.015 mM. All the compounds showed suitable drug like characteristics according to Lipinskis rule.

Quinazoline-sulfonamides with potent inhibitory activity against the α-carbonic anhydrase from Vibrio cholerae

Thirteen novel sulfonamide derivatives incorporating the quinazoline scaffold were synthesized by simple, eco-friendly procedures. These compounds were tested for their ability to inhibit the α-carbonic anhydrases (CA, EC 4.2.1.1) from Vibrio cholerae (VchCA) as well as the human α-CA isoforms, hCA I and hCA II. Nine compounds were highly effective, nanomolar inhibitors of the pathogenic enzyme VchCA. Three of them were also highly effective sub-nanomolar inhibitors of the cytosolic isoform II. The best VchCA inhibitor had a KI of 2.7 nM. Many of these developed compounds showed high selectivity for inhibition of the bacterial over the mammalian CA isoforms, with one compound possessing selectivity ratios as high as 97.9 against hCA I and 9.7 against hCA II. Compound 9d was another highly effective VchCA inhibitor presenting a selectivity ratio of 99.1 and 8.1 against hCA I and hCA II, respectively. These results suggest that sulfonamides with quinazoline backbone could be considered suitable tools to better understand the role of bacterial CAs in pathogenesis.