حیل فقہ اسلامی كے تناظر میں

Abstract: Heela (-f*) is an Arabic word used as a term in Islamic Jurisprudence. In English language it can be explained "evasiveness" which can be interrupted in to ways as a person may understand something else than the meaning ofspeaker without labelling the lie. It demands wisdom and minuteness to be usedfor achieving the objectives. It legitimately lawful evasiveness and sinful evasiveness all two dimensions fit. The valid evasiveness fulfill all the legal requirements. It has further three types. Infirst type although evasiveness may be invalid but the achieved purpose must be lawful and valid. For example, a woman, who hasfiledfor divorcedfrom her husband can present before jury the fake witness, in order to achieve her purpose. In second type an evasiveness may be used as mean of profit or hurdlefrom getting a loss. It has the relation ofcause and effect. While in third type it has an element ofambiguity, which may be used to avoid the loss by misleading or giving false statement. Sinful evasiveness is the one which is used to achieve an illegal target. It is further divided into three types. In first type the evasiveness and the required purpose both stand illegal. In second type the evasiveness may be lawful but the targeted objective is unlawful. While in third type the evasiveness and the purpose both may be valid but these are manipulated to achieve an illegal purpose and objective.

Studies on Anticancer and Antileishmanial Potentials of Synthetic Compounds and Insight into Anticancer Mechanism of Selected Organotin Iv Compounds

Drug development has multiple stages of drug designing and evaluation in pharmacological models for desired clinical outcomes. The unmet need to completely eradicate cancer and leishmaniasis drives researchers to continue the struggle for safer and effective medicines. Along these lines, a library of 78 organic synthetic compounds including organotin (IV) (39), indoline (15), hydrazide (4), diazole (2) and ferrocene (18) derivatives were studied against Leishmania and cancer using in vitro, in silico and in vivo models. Cytotoxicity against DU145, THP-1 and isolated lymphocytes was shown by 36 (> 70%), 21 (> 50-70%), and 18 (least IC50 2.23 µg/ml) organotins and 1 (75.72%), 4 (50.2-82.3%) and 2 (least IC50 13 µg/ml) indolines, respectively. Only 5 (50.08-81.7%) hydrazides/diazoles and 9 (least IC50 6.66 µg/ml) ferrocenes were cytotoxic to THP-1 cells and lymphocytes, respectively. A total of 38 (least MIC 0.0122 µg/disc) organotins, 1 (least MIC 3.125 µg/disc) indoline, 3 (least MIC 1.5625 µg/disc) diazole/hydrazides and 17 (least MIC 0.74 µg/disc) ferrocenes demonstrated protein kinase (PK) inhibition activity in Streptomyces 85E. Next, in silico analysis of selected 36 organotin (IV) compounds, comparatively more cytotoxic to cancer cells, showed that these were druglike to mid structures, have low to high blood brain barrier penetration and human intestinal absorption (caco2 cell permeability 17.6-35.09 nm/sec) and were metabolized by phase I and phase II reactions. Organotins were also predicted to target multiple enzymes, transcription factors, receptors, transporters, ion channels and other proteins. Subsequently, in vitro cytotoxicity analysis in prostate cancer cell lines and fibroblasts provided least IC50 values of 0.17 µM (PC3M) and 1.67 µM (fibroblasts) for triphenyltin (IV); 0.63 µM (PC3M) and 0.12 µM (fibroblasts) for tributyltin (IV); 0.33 µM (PC3M) and 2.55 µM (fibroblasts) for dibutyltin (IV) and 6.06 µM (PC3M) and 4.29 µM (fibroblasts) for tribenzyltin (IV) compounds after 72 h of treatment. Eventually, in-depth study of two most active compounds namely dibutylstannanediyl (2Z,2’Z)-bis(4(benzylamino)-4-oxobut-2-enoate (Ch-620) and triphenylstannyl 2-(benzylcarbamoyl) benzoate (Ch-319), showed that both compounds were more cytotoxic to prostate cancer and melanoma cells as compared to normal cells, restricted their colony forming capacity and migration, induced cell cycle arrest and caspase mediated apoptosis and disrupted associated regulatory proteins. Ch-620 resulted in phosphorylation of p38 MAPK and ERK1/2, upregulation of PPARα, decreased expression of SMAD4 and ITGB5 and reduced tumor proliferation as observed by proteomics, in vitro and in vivo xenograft studies. Treatment of cancer cells and transgenic Pten knockout mice with Ch-319 downregulated PI3K/Akt signaling associated with elevation of FOXO3a expression. In addition, Ch-319 decreased expression of epithelial-mesenchymal transition markers Ncadherin and Vimentin with concomitant increase in E-cadherin in in vitro. Immunohistochemical examination of tumor sections also depicted reduction of proliferation markers. Moreover, evaluation of 78 compounds against Leishmania tropica kwh showed that 37, 5 and 1 organotin, indoline and ferrocene compounds, respectively inhibited growth of promastigotes. The selected 43 compounds predominantly organotin (IV) derivatives, halted the growth of Leishmania promastigotes partially by producing reactive oxygen species. Antileishmanial activity was reduced by 4.1-6.9 and 1.4-7.96% in triphenyltin (IV), 3.3-14.22 and 6.3-11.2% in tribenzyltin (IV), 5.2-34.38 and 1.838.2% in tributyltin (IV) and 7.9-15.7 and 5.2-15.4% in dibutyltin (IV) compounds in the presence of sodium azide and mannitol, respectively. Indolines and ferrocenes demonstrated antileishmanial activity reduction maximally in the presence of mannitol by 5.3 and 6.22%, respectively. Considering all these results, it is proposed that Ch-319 and Ch-620 have potential to be developed as anticancer agents against prostate cancer. Furthermore, organotin (IV) compounds in particular are also potent antileishmanial agents and detailed analysis on their mechanism is recommended.